Journal of the Renin-Angiotensin-Aldosterone System

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

Wenzhuang Tang, Tian-Biao Zhou and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

JRAAS 1470320314563426, first published 18 December 2014. DOI: 10.1177/1470320314563426.

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

JRAAS 1470320314563424, first published 18 December 2014. DOI:10.1177/1470320314563424.

Weiqiang Zhong, Zongpei Jiang and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

JRAAS1470320314566019, first published 26 January 2015. DOI: 10.1177/1470320314566019.

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

JRAAS 1470320314563425, first published 1 February 2015. DOI:10.1177/1470320314563425.

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

JRAAS 1470320314566221, first published 1 February 2015. DOI: 10.1177/1470320314566221.

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

JRAAS 1470320314568521, first published 3 February 2015. DOI: 10.1177/1470320314568521.

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

JRAAS March 2015; 16: 165–171, first published 14 November 2014. DOI: 10.1177/1470320314557849.

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

JRAAS September 2015; 16: 660–665, first published 20 August 2014. DOI: 10.1177/1470320314524011.

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System Septembr 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

The renin angiotensin system (RAS) is closely related to the cardiovascular system, body fluid regulation and homeostasis.

Despite common therapeutic methods, stem cell/progenitor cell therapy is daily increasing as a term of regenerative medicine. RAS and its pharmacological inhibitors are not only involved in physiological and pathological aspects of the cardiovascular system, but also affect the different stages of stem cell proliferation, differentiation and function, via interfering cell signaling pathways.

This study reviews the new role of RAS, in particular Ang II distinct from other common roles, by considering its regulating impact on the different signaling pathways involved in the cardiac and endothelial tissue, as well as in stem cell transplantation.

This review focuses on the impact of stem cell therapy on the cardiovascular system, the role of RAS in stem cell differentiation, and the role of RAS inhibition in cardiac stem cell growth and development.

Polymorphisms of the angiotensin converting enzyme (ACE) gene can interfere with exercise-induced acute blood pressure (BP) reduction. This cross-over study investigated the acute effect of a single walk on BP and tested whether polymorphisms of the ACE gene might explain the variation in BP responses.

Thirty-four healthy medicated individuals were randomized to one control and one walking session at 60–75% of heart rate reserve. Subjects left the laboratory wearing an ambulatory BP monitor until waking the next morning.

Overall, systolic BP was somewhat lower following the walking session (p=.06), which could be attributed to a consistently lower systolic BP for 5 h after exercise (p-interaction<.04) compared with control rest. Similarly, II/ID individuals had a lower systolic BP (p-interaction=.02) and diastolic BP (p-interaction<.01) for 5 h after walking compared with control rest. Among DD individuals, a single walk did not induce a reduction in BP (p-interaction>.05).

Our results showed that postexercise hypotension can occur after a walk at moderate intensity in carriers of the I allele; we were not able to demonstrate this in DD individuals. Our results suggest that genetic variation in the ACE gene might affect the BP response to exercise, although more research is needed to confirm these findings.

Experimental evidence suggests that aldosterone directly contributes to organ damage by promoting cell growth, fibrosis, and inflammation. Based on these premises, this work aimed to assess the glomerular effects of aldosterone, alone and in combination with salt.

After undergoing uninephrectomy, 75 rats were allocated to five groups: control, salt diet, aldosterone, aldosterone + salt diet, aldosterone + salt diet and eplerenone, and they were all studied for four weeks. We focused on glomerular structural, functional, and molecular changes, including slit diaphragm components, local renin–angiotensin system activation, as well as pro-oxidative and profibrotic changes.

Aldosterone significantly increased systolic blood pressure, led to glomerular hypertrophy, mesangial expansion, and it significantly increased the glomerular permeability to albumin and the albumin excretion rate, indicating the presence of glomerular damage. These effects were worsened by adding salt to aldosterone, while they were reduced by eplerenone. Aldosterone-induced glomerular damage was associated with glomerular angiotensin-converting enzyme (ACE) 2 downregulation, with ACE/ACE2 ratio increase, ANP decrease, as well as with glomerular pro-oxidative and profibrotic changes.

Aldosterone damages not only the structure but also the function of the glomerulus. ACE/ACE2 upregulation, ACE2 and ANP downregulation, and pro-oxidative and profibrotic changes are possible mechanisms accounting for aldosterone-induced glomerular injury.

In this study, we investigated whether AngII receptors (AT1a and AT2) contributed to the development of the aldosterone-induced inflammatory response of rat mesangial cells (RMCs).

RMCs were isolated from the glomeruli of normal or diabetic rats which were produced by injection of streptozotocin, and cultured in high-glucose media. In order to evaluate the effects of aldosterone, the expression of AT1a, AT2, NF-κB and MCP-1 was detected. In addition, in order to evaluate the role of Ang II receptors, AT1a and AT2 genes were blocked and the expression of NF-κB and MCP-1 was detected. Moreover, for assessing the relationship between NF-κB and MCP-1, the NF-κB gene was blocked and MCP-1 expression was detected.

Aldosterone significantly increased AT1a, AT2, NF-κB and MCP-1 levels in RMCs in a dose-dependent manner, whereas eplerenone (EPI), a selective aldosterone antagonist, partly inhibited the effects of aldosterone. When AT1a and AT2 genes were blocked, the expression of NF-κB and MCP-1 was greatly inhibited. Moreover, when the NF-κB gene was silenced, the expression of MCP-1 was reduced.

We demonstrated that aldosterone induced an inflammatory response in RMCs cultured in high-glucose media via the AT1a and AT2 pathways.

Binge eating disorder (BED) is associated with dopaminergic activation as food reward, resulting in metabolism-related disorders. Stimulation of angiotensin type 2 (AT₂) receptor is reported to inhibit dopamine synthesis. We investigated the possible roles of AT₂ receptor-mediated dopamine regulation in the pathogenesis of BED.

Male C57BL/6 mice, type 2 diabetic (KKAy) mice and AT₂ receptor-null (AT₂KO) mice at eight weeks old were treated with AT₂ receptor agonist, compound 21 (C21) or saline for two weeks. Mice were subjected to fasting for two days followed by re-feeding for seven days.

Treatment with C21 attenuated the rebound proportion of body weight, food intake and water intake in KKAy mice, but not in C57BL/6 and AT₂KO mice. Dopamine concentration in the striatum was further increased by fasting in KKAy and AT₂KO mice. Administration of C21 significantly attenuated this fasting-induced increase in dopamine level only in KKAy mice. Dopamine receptor D1, D2 expression in the substantia nigra were markedly lower in KKAy mice compared with C57BL/6 mice, while administration of C21 increased their expression in KKAy mice.

Our study suggests that AT₂ receptor stimulation may be a new therapeutic approach to improve eating disorder associated with dopamine resistance.

Recently we established that pro-inflammatory actions of angiotensin (Ang) II in astrocytes involved Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and interleukin-6 (IL-6).

In our current study, we determined in brainstem and cerebellum whether Ang III also activates STAT3 leading to IL-6 mRNA expression and astrocyte proliferation.

Ang III induced STAT3 phosphorylation in a concentration- and time-dependent manner. Significant STAT3 phosphorylation was rapid and was maximal within 10 min, and with 100 nM Ang III. The Ang AT₁ receptor was shown to mediate this action of Ang III. Ang III also significantly induced IL-6 mRNA expression within an hour, and maximal Ang III-mediated IL-6 mRNA expression occurred in the presence of 100 nM Ang III. Ang III-mediated IL-6 mRNA expression occurred by the interaction of the peptide with the Ang AT₁ receptor and was mediated by STAT3. In addition, STAT3 was shown to mediate Ang III astrocyte proliferation.

These findings suggest that Ang III, similar to Ang II, has pro-inflammatory effects since it induces STAT3 leading to an induction of IL-6 mRNA expression, outcomes that lend relevance to the physiological importance of central Ang III.

Several reports suggest that the use of angiotensin receptor blockers (ARBs) is associated with lung cancer (LC) reduction. However, the results were contradictory.

Four online databases were searched. The strength of the association between ARB and the risk of LC was measured by odds ratio (OR) and 95% confidence interval (CI). OR was analyzed by random-effects model.

Eight studies with 298000 subjects were included in this meta-analysis. Using of ARB was significantly associated with decreased LC risk (OR = 0.81; 95% CI 0.69–0.94; p = 0.005). In the subgroup analysis by race, Asians treated with ARB showed decreased LC risk (OR = 0.60; 95% CI 0.54–0.67; p < 0.00001). However, Caucasians treated with ARB did not show significantly decreased LC risk (OR = 0.90; 95% CI 0.79–1.02; p = 0.11). Subgroup analysis by duration of follow-up was conducted. The studies with less than 5 years showed significant result (OR = 0.79; 95% CI 0.64–0.97;p = 0.02). However, the studies with more than 5 years did not show significantly decreased LC risk (OR = 0.84; 95% CI 0.61–1.16; p = 0.29).

This meta-analysis indicated that ARBs may be associated with decreased risk of LC.

Previous studies demonstrated that stimulation of angiotensin subtype 1 receptor (AT₁R) led to increased renal generation of prostaglandins E₂ (PGE₂) and renal inflammation. In turn, PGE₂ increases AT₁R activity. The conversion of PGE₂ to the less active metabolite prostaglandin F_2α (PGF_2α) via 9-ketoreductase interrupts this feedback loop. The effects of diabetes on the interface between AT₁R, PGE₂ and PGF_2α are not well established. We hypothesized that in diabetes, an aberrant AT₁R activity enhances the biosynthesis of PGE₂ and impairs the activity of PGE 9-ketoreductase, leading to accumulation of PGE₂.

Using microdialysis technique, we monitored renal interstitial fluid levels of angiotensin II (Ang II), PGE₂ and PGF_2α in control and AT₁R blocker, valsartan, treated diabetic rats (N=8 each). We utilized the PGF_2α to PGE₂ ratio as indirect measure of PGE 9-ketoreductase activity.

Diabetes increased renal interstitial fluid levels of Ang II, PGE₂ and PGF_2α. PGF_2α/PGE₂ ratio increased by the third week, but declined by the sixth week of diabetes. Valsartan reduced PGE₂ and PGF_2α levels and increased Ang II and the conversion of PGE₂ to PGF_2α.

Our results suggest that in diabetes, AT₁R increases PGE₂ generation and reduces conversion of PGE₂ to PGF₂α with the progression of diabetes.

Some studies have assessed the association between angiotensin-converting enzyme (ACE) I/D polymorphism and acute respiratory distress syndrome (ARDS) risk. However, the results have been inconclusive and contradictory. Therefore, we performed a meta-analysis to investigate the association between ACE I/D polymorphism and ARDS risk.

All relevant studies were searched using PubMed and EMBASE. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models or fixed-effects models.

A total of 14 studies with 5218 subjects were included in this meta-analysis. We found that ACE I/D polymorphism significantly associated with an increased ARDS risk (OR=1.57; 95% CI 1.30–1.89; P<0.00001). In the subgroup analysis by race, Caucasians with ACE I/D polymorphism showed increased ARDS risk (OR=1.63; 95% CI 1.32–2.02; P<0.00001). However, Asians with this polymorphism did not show significantly increased ARDS risk (OR=1.31; 95% CI 0.90–1.90; P=0.95). In the subgroup analysis by age group, adults showed increased ARDS risk (OR=1.60; 95% CI 1.32–1.93; P<0.00001), while pediatric patients did not have increased ARDS risk (OR=1.15; 95% CI 0.57–2.30; P=0.70).

This meta-analysis suggested that ACE I/D polymorphism might contribute to the susceptibility for ARDS.

Several molecular epidemiological studies have been conducted to examine the association between angiotensin-converting enzyme (ACE) I/D polymorphism and diabetic peripheral neuropathy (DPN) risk. However, the conclusions remained controversial. We therefore performed this meta-analysis.

PubMed and EMBASE were searched to identify case-control studies investigating the associations of ACE I/D polymorphism with risk of DPN. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between ACE I/D polymorphism and risk of DPN.

A total of seven case-control studies including 1316 cases and 1617 controls were included. ACE I/D polymorphism was associated with a significantly increased risk of DPN (OR=1.46, 95%CI 1.11–1.92, p=0.006, I²=48%). This result remained statistically significant when the adjusted ORs were combined (OR=1.84, 95%CI 1.14–2.99, p=0.01, I²=53%). In the subgroup of ethnicity, a significantly elevated risk was observed in Caucasians (OR=1.32, 95%CI 1.10–1.59, p=0.003, I²=43%).

Our meta-analysis confirmed that ACE I/D polymorphism was associated with the risk of DPN.

The renin-angiotensin-aldosterone system is important to the development of atrial fibrillation (AF). A lot of research has focused on the relationship between angiotensin-converting enzyme (ACE) insertion (I) /deletion (D) gene polymorphisms and AF, with inconsistent results. A meta-analysis was carried out to find the correlation between ACE I/D gene polymorphisms and AF.

Data were extracted from articles published before September 2013 on ACE I/D polymorphisms and AF in Embase, PubMed, WanFangData, and China National Knowledge Infrastructure.

The recessive model found that ACE I/D gene polymorphisms were related to AF (odds ratio (OR) = 1.61, 95% confidence interval (CI) = 1.16–1.72). Subgroup analysis showed a significant association in the recessive model for Asian (OR = 1.40, 95% CI = 1.19–1.80) and Caucasian (OR = 1.42, 95% CI = 1.01–1.99) populations.

ACE I/D gene polymorphisms and AF are significantly related to ethnicity. Individuals with the ACE D/D genotype appear to be at higher risk of AF.

Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function.

Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook’s pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman’s method.

Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme.

The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination.

The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and renal allograft survival after renal transplantation from the published reports are still debatable. This study was performed to evaluate the relationship between the ACE I/D gene polymorphism and renal allograft survival after renal transplantation using meta-analysis.

Eligible studies were identified from PubMed and Cochrane Library on 1 November 2014, and eligible studies were recruited and synthesized using a meta-analysis methodology.

Twelve investigations were included in this meta-analysis for the assessment of the relationship between the ACE I/D gene polymorphism and renal allograft survival. In this meta-analysis, the ACE I/D gene polymorphism was not associated with renal allograft survival after renal transplantation for overall populations, Caucasians, Brazilians and Africans. Interestingly, the ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population.

ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. However, more studies should be performed to confirm this association.

Many studies have focused on the relationship between the angiotensin-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism and pancreatitis risk, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between ACE I/D polymorphism and pancreatitis risk.

Relevant publications were searched in several widely used databases and seven studies from six eligible articles were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between ACE I/D polymorphism and pancreatitis risk.

Significant associations between ACE I/D polymorphism and pancreatitis risk were observed in both overall meta-analysis for DI versus II (OR=0.80, 95% CI=0.67–0.96) and DD + DI versus II (OR=0.83, 95% CI=0.70–0.98), and acute pancreatitis subgroup for DI versus II (OR=0.65, 95% CI=0.44–0.95). However, no significant pancreatitis risk variation was detected for all genetic models in the subgroup meta-analysis based on ethnicity.

According to the results of our meta-analysis, the ACE I/D polymorphism probably associates with pancreatitis risk, especially acute pancreatitis risk, with the I allele acting as a risk factor.

Polymorphisms in the apolipoprotein B (apoB) gene have been reported to be associated with coronary heart disease (CHD). However, the results on this topic are conflicting. The present study aims to derive a more precise estimation of the relationship between CHD and apoB genetic polymorphisms by meta-analysis.

We identified a total of 54 studies involving 7236, 10,912, and 14,102 individuals, respectively, for EcoRI, XbaI, and SpIns/Del polymorphisms by searching in PubMed, Web of Science, Google Scholar, the Cochrane Library, Wanfang Data, SinoMed, and CNKI. We utilized RevMan 5.0 software to perform the meta-analyses.

A significant statistical association between apoB EcoRI polymorphism and CHD was observed under an allelic (p = 0.001, odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.12–1.57), dominant (p = 0.005, OR = 1.22, 95% CI = 1.06–1.40), and recessive (p = 0.04, OR = 1.33, 95% CI = 1.01–1.74) model. We also found similar association of apoB SpIns/Del polymorphism with CHD. However, we did not find association between apoB XbaI polymorphism and CHD.

The current meta-analysis found an association of EcoRI polymorphism and SpIns/Del polymorphism with an increased risk of CHD. No significant association between apoB XbaI polymorphism and CHD we observed in the present study.

Polymorphisms of angiotensin converting enzyme (ACE) and methylene-tetrahydrofolate reductase (MTHFR) genes have been proposed to be associated with type 2 diabetes mellitus (T2DM) with conflicting results. This work was planned in order to check for the association of these polymorphisms with the susceptibility for and complications of T2DM among Egyptian cases.

This is a case controlled study involving 203 patients with T2DM and 311 healthy controls. Polymorphic variants of ACE I>D and MTHFR (677 C>T and 1298 A>C) were determined using the polymerase chain reaction (PCR) restriction analysis technique.

The susceptibility to T2DM was higher among subjects having the MTHFR 677TT (odds ratio (OR)=2.2, p=0.01), MTHFR 1298 AA (OR=1.84, p=0.001) and ACE (ID+II) (OR=2.0, p=0.0007) genotypes. Logistic regression analysis showed that MTHFR 677T allele was a risk factor for diabetic retinopathy (DR) (OR=3.47, p<0.001), diabetic polyneuropathy (DPN) (OR=5.2, p<0.0001) and ischemic heart disease (IHD) (OR=2.9, p<0.05), while MTHFR 1298 C allele was a risk factor for DR (OR=4.2, p<0.001) and the ACE DD genotype was a risk factor for DPN (OR=3.1, p<0.001).

The MTHFR 677 TT genotype was associated with T2DM susceptibility and complications (DR, DPN and IHD). The MTHFR 1298 CC, AC and ACE DD genotypes were associated with DR and DPN.

Previous case-control studies on the relationship between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and coronary restenosis did not reach the same conclusion. In the present study, we aimed to further evaluate the relationship between the ACE gene I/D polymorphisms and coronary restenosis, after percutaneous coronary intervention (PCI).

By searching PubMed, EMBase, the Chinese Biomedical Literature Database and Wanfang database, we selected 16 case-control studies related to ACE gene I/D polymorphism and coronary restenosis after PCI. To test for heterogeneity in each study, we utilized the Q-test and I² test. To merge the odds ratio (OR) and 95% CI, we utilized the random effects model during the analyses.

The present study included 4693 subjects: 1241 patients with coronary restenosis and 3452 without coronary restenosis. By meta-analysis, we found there was significant association of ACE gene I/D polymorphism with coronary restenosis (D allele versus I allele: OR = 1.92; 95% CI (1.40–2.43); p < 0.001). A subgroup analysis, by stratification according to ethnicity, also showed that this association was found not only in the Caucasian population ((D allele versus I allele: OR = 1.94; 95% CI (1.38–2.80); p < 0.001)), but also in the Asian population ((D allele versus I allele: OR = 1.83; 95% CI (1.05–3.20); p = 0.03)). After stratification according to age, we found that the D allele carriers have a higher risk for development of coronary restenosis in subjects < 60 years old (OR = 2.13; 95% CI: 1.40–3.24; p = 0.0004); while in the subjects ⩾ 60 years old, the association was present with bordering significance (OR = 1.48; 95%CI: 0.98–2.25; p = 0.06).

The present study suggested that the ACE gene I/D polymorphism was associated with coronary restenosis, regardless of age and ethnicity.

Previous studies on the relationship between angiotensin ІІ type 1 receptor (AT1R) gene (A1166C) polymorphism and breast cancer did not reach the same conclusion. In the present study, we aimed to further evaluate the relationship between the AT1R gene A1166C polymorphism and breast cancer risk.

We selected five case-control studies related to AT1R gene A1166C polymorphism and breast cancer by searching PubMed, EMBase, Chinese Biomedical Literature Database, Chinese CNKI, Web of Science, and the Wanfang database. We utilized Q-test and I² test to detect the heterogeneity between each study. A random-effects model (I² > 50%; p < 0.10) or a fixed-effects model (I² < 50%; p > 0.10) was utilized to merge the odds ratio (OR) and 95% confidence interval (CI) during the meta- analyses.

The present study included 972 patients with breast cancer and 1336 cancer-free control subjects. By meta-analysis, we found A1166C polymorphism was associated with decreased risk for breast cancer in Caucasian population in an additive model (C vs. T: OR = 0.77, 95% CI: 0.62–0.96, p = 0.02). However, we did not find associations in other genetic models (AC+CC vs. AA: OR = 0.78, 95% CI: 0.50–1.22, p = 0.28; CC vs. AA+AC: OR = 1.64, 95% CI: 0.94–2.85, p = 0.08).

We concluded that AT1R gene A1166C polymorphism was associated with reduced risk for breast cancer.

Aldosterone synthase (CYP11B2) is one of the most studied candidate genes related to essential hypertension (EH) and left ventricular hypertrophy (LVH). Some studies have focused on the relationship between −344C/T polymorphism (rs1799998) in the CYP11B2 gene and LVH, but the results are controversial. This meta-analysis is purposed to reveal the relationship between the −344C/T and the left ventricular structure and function, including left ventricular end diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular mass/left ventricular mass index (LVM/LVMI), left ventricular posterior wall thickness (LVPWT), and interventricular septal wall thickness (IVS).

A literature search of PubMed and Embase databases was conducted on articles published before January 27, 2014. The odds ratios with 95% confidence intervals were calculated. Heterogeneity analyses were performed using meta-regression. Tests for publication bias were also performed and biased studies should be removed from subsequent analyses.

There were 20 studies with a total of 6780 subjects meeting the inclusion criteria. The main finding was that concentration levels of LVEDD and LVESD were higher in CC homozygous individuals than in TT homozygous individuals in the whole group. In the Asian subgroup, TT homozygous individuals had larger IVS than CC homozygous individuals. In the Caucasian normotension subgroup, CC homozygous individuals had larger LVM/LVMI than TT homozygous individuals. In the Asian essential hypertension subgroup, TT homozygous individuals had larger LVPWT values than CC homozygous individuals.

The present findings support the hypothesis that CC homozygous individuals may have greater left ventricular diameters (LVEDD and LVESD) regardless of their ethnicities or physical conditions.

Several studies show that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with hypertension in various populations. The present study sought to determine the association of the I/D gene polymorphism among Malay male essential hypertensive subjects in response to ACE inhibitors (enalapril and lisinopril).

A total of 72 patients with newly diagnosed hypertension and 72 healthy subjects were recruited in this study. Blood pressure was recorded from 0 to 24 weeks of treatment with enalapril or lisinopril. Genotyping of the I/D polymorphism was carried out using a standard PCR method.

Statistically significant association of the D allele of the ACE gene was observed between the case and control subjects (p < 0.01). There was a decrease in blood pressure in the patients carrying the DD genotype (SBP=18.5±8.1 mmHg, DBP=15.29±7.1 mmHg) rather than the ID (SBP=4.1±3.3 mmHg, DBP=9.1±3.5 mmHg) and II genotypes (SBP= 3.0±0.2 mmHg, DBP 0.11±6.1 mmHg) of the ACE gene.

Patients carrying the DD genotype had higher blood pressure-lowering response when treated with ACE inhibitors enalapril or lisinopril than those carrying ID and II genotypes, suggesting that the D allele may be a possible genetic marker for essential hypertension among Malay male subjects.

Polymorphisms in angiotensin II type-1/2 receptor genes (AGTR1/AGTR2) may be involved in the pathogenesis of primary aldosteronism. The present study aims to reveal some loci susceptible to the disease on the genes in a group of Chinese Han nationality.

A case-control study was conducted in 202 patients and 188 controls. Ten tagging SNPs on AGTR1/AGTR2 were genotyped for all subjects via the method of multiplex PCR-ligase detection reaction. Statistical analysis was performed with chi-square test and logistic regression analysis.

rs3772616 on the AGTR1 gene was a factor for susceptibility to primary aldosteronism (p<0.001), and the TT genotype significantly decreased the risk of primary aldosteronism compared with the CC homozygote (p=0.008, adjusted OR=0.13; 95%CI: 0.03–0.59). The rs3772616 polymorphism was associated with primary aldosteronism under the additive and dominant models. The female carriers of the G allele in rs5193 showed a significant difference compared with the T allele.

The AGTR1 rs3772616 polymorphism can be considered as a hereditary marker for primary aldosteronism, and in the Chinese Han population the rs5193 G allele seems to predispose to it only in women.

Previous studies showed that genetic variants of the angiotensinogen (AGT) gene conferred higher risk for acquired atrial fibrillation (AF). The present study investigated whether AGT variants correlate with the clinical outcome in patients with acquired AF after catheter ablation (CA).

A total of 150 acquired symptomatic drug-refractory AF patients (mean age 63.7±11.0 years, 24.6% non-paroxysmal AF) with acquired AF underwent a single CA procedure in our department and were included in this retrospective analysis. Eight tagging single nucleotide polymorphisms (tSNPs) in the AGT gene were genotyped. Standard electrocardiographs (ECGs) and 24-hour Holter recordings were performed during a median follow-up period of 57.5 months to detect AF recurrence.

Sixty-one patients (40.7%) suffered AF recurrences after a single CA procedure during follow up. Of the eight tSNPs, the frequency of the M allele of M235T was significantly higher in the recurrence group (28%) compared to the non-recurrence group (18%) (p=0.042). The recurrence rates of patients with the TT, MT, and MM genotypes were 34.4%, 50%, and 55.6%, respectively (p_trend=0.049). After adjusting for age, sex, body mass index, hypertension, left atrial volume index (LAVI) and other covariates, M235T increased the risk of AF recurrence in additive and dominant models with odds ratios of 2.023 (95% confidence interval (CI): 1.034–3.926, p=0.033) and 2.601 (95% CI: 1.102–6.056, p=0.025), respectively. However, in multiple correction analyses, the p values of multiple comparisons were not statistically significant (p_correct>0.05).

The M allele of M235T might be associated with an increased risk of AF recurrence after CA. Genotyping may thus be helpful on identifying patients with higher risks of AF recurrence after CA and developing optimal follow-up strategies. These strategies may differ and should be individualized according to patients’ genotype. Future studies are warranted to validate the potential effect of AGT M235T on AF recurrence post CA.

Previous studies have shown that angiotensin II AT1 receptor gene (AT1R) polymorphisms are associated with the risk for hypertension. However, the results remain controversial. In the present study, we performed a meta-analysis to systematically summarize the association between AT1R genetic polymorphisms and the risk for hypertension.

We searched the literature in PubMed, EMBASE, ISI Web of Science, Wanfang, and Chinese National Knowledge Infrastructure databases (CNKI) to find case-control studies on the associations of AT1R genetic polymorphisms with the risk for hypertension. The meta-analysis was performed by using RevMan 5.0 software. The association of hypertension risk with AT1R genetic polymorphism was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs).

Fifty-six studies involving 28,952 subjects were included in the present meta-analysis. Our results suggest that the polymorphism (A1166C) of AT1R gene is associated with a statistically increased hypertension risk, not only in Asian populations but also in Caucasian populations. We did not find any association in African populations.

This meta-analysis suggests that A1166C polymorphism in the AT1R gene is associated with the risk of hypertension in Asian and Caucasian populations.

The D allele of the common angiotensin-converting enzyme (ACE) I/D gene polymorphism (rs4646994) predisposes to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, results on which allele predisposes to disease susceptibility remain controversial in Asian populations. This study was performed to evaluate the association of the common ACE I/D gene polymorphism with both T2DM and CVD susceptibility in an Arab population.

We genotyped the ACE I/D polymorphisms by direct allele-specific PCR in 183 healthy controls and 400 CVD patients with diabetes (n=204) and without (n=196). Statistical analysis comparing between the different groups were conducted using R statistic package “SNPassoc”.

Two genetic models were used: the additive and co-dominant models. The I allele was found to be associated with T2DM (OR=1.84, p=0.00009) after adjusting for age, sex and body mass index. However, there was no association with CVD susceptibility (p>0.05).

The ACE I allele is found to be associated with T2DM; however, no association was observed with CVD. The inconsistency between studies is suggested to be attributed to genetic diversity due to the existence of sub-populations found in Asian populations.

Tardive dyskinesia is a serious motor disorder of the orofacial region, resulting from chronic neuroleptic treatment of schizophrenia. Candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) has been reported to possess antioxidant and neuroprotective effects. The present study is designed to investigate the effect of candesartan and lisinopril on haloperidol-induced orofacial dyskinesia and oxidative damage in rats.

Tardive dyskinesia was induced by administering haloperidol (1 mg/kg i.p.) and concomitantly treated with candesartan (3 and 5 mg/kg p.o.) and lisinopril (10 and 15 mg/kg p.o.) for 3 weeks in male Wistar rats. Various behavioral parameters were assessed on days 0, 7, 14 and 21 and biochemical parameters were estimated at day 22.

Chronic administration of haloperidol significantly increased stereotypic behaviors in rats, which were significantly improved by administration of candesartan and lisinopril. Chronic administration of haloperidol significantly increased oxidative stress and neuro-inflammation in the striatum region of the rat’s brain. Co-administration of candesartan and lisinopril significantly attenuated the oxidative damage and neuro-inflammation in the haloperidol-treated rat.

The present study supports the therapeutic use of candesartan and lisinopril in the treatment of typical antipsychotic-induced orofacial dyskinesia and possible antioxidant and neuro-inflammatory mechanisms.

Hypertension guidelines recommend fixed-dose combinations for enhanced blood pressure (BP) reduction and compliance. The objective of this study was to assess the effectiveness and safety of fixed-dose perindopril/amlodipine combination in reducing and controlling BP in Greek hypertensive patients, as well as the effect of baseline BP and added cardiovascular risk on BP reduction.

This 6-month prospective observational study included male or female patients ⩾18 years with essential hypertension prescribed fixed-dose combination perindopril/amlodipine. BP was measured at baseline and 3 and 6 months. Baseline cardiovascular risk and treatment compliance were also assessed.

In 2231 per protocol patients, mean systolic BP decreased from 157.0±15.4 mm Hg to 129.0±7.9 mm Hg after 6 months, and diastolic BP from 91.5±10.1 to 78.8±6.7 mm Hg (both p < 0.001). BP control was achieved in 84.8% at 6 months. Patients with higher baseline added cardiovascular risk or BP had greater BP reduction (p < 0.001). Compliance was good (97.1% took treatment “every day” or “quite often”) and few (n = 27; 1.2%) discontinued treatment prematurely due to adverse events.

Fixed-dose perindopril/amlodipine safely and effectively reduced high BP in real-life practice, achieving BP control in most patients. About half of Greek hypertensive patients have high/very high added cardiovascular risk.

Bone marrow (BM) Angiotensin II (Ang II) type 1 (AT₁) receptor plays a crucial role in atherosclerosis development; however, the effect of BM Ang II type 2 (AT₂) receptor on atherogenesis remains undefined.

We generated BM chimera apoE-deficient (apoE^−/−) mice whose BM cells were repopulated with AT₂-deficient (Agtr2^−/−) or wild-type (Agtr2^+/+) cells. After 2 months of a high-cholesterol diet, the atherosclerotic lesion area was significantly increased in the apoE^−/−/BM-Agtr2^−/− mice compared with the apoE^−/−/BM-Agtr2^+/+ mice (51%, P < 0.05), accompanied by an augmented accumulation of lesion macrophages. Although phenotypic polarization in BM-derived macrophages and lipopolysaccharide-induced expression of proinflammatory cytokines in thioglycollate-induced peritoneal macrophages (TGPMs) were not affected by AT₂-deficiency, mRNA and protein expression levels of macrophage liver X receptor β (LXRβ) were significantly decreased in Agtr2^−/− TGPMs compared with Agtr2^+/+ TGPMs. Anti-inflammatory effects of LXR agonist (GW3965) were markedly inhibited in Agtr2^−/− TGPMs. Furthermore, the expression levels of ATP-binding cassette transporter ABCA1 and CCR7 were much lower in Agtr2^−/− TGPMs than Agtr2^+/+ TGPMs, accompanied by a significantly reduced cholesterol efflux.

Our findings demonstrate that BM-AT₂ deficiency aggravates atherosclerosis, at least in part, by eliminating the anti-atherogenic properties of macrophages elicited by LXRβ activation.

Tonin is an enzyme that is able to generate angiotensin II (Ang II) from angiotensin I (Ang I) or directly from angiotensinogen. Our goal was to characterize the renal renin-angiotensin system in transgenic mice that express rat tonin (TGM`(rTon)).

Mice were euthanized and the kidneys removed for analysis. Tonin activity was evaluated by radioimmunoassay and angiotensin I-converting enzyme (ACE) activity by HPLC. Tonin, ACE and angiotensin II-converting enzyme (ACE2) expression was analyzed by Western blotting.

Tonin activity was significantly increased in TGM`(rTon) compared to their respective wild-type (WT) littermates (1.7 ± 0.21 vs 0.11 ± 0.02 nmol of Ang II/min/mg of protein). Tonin activity had a strong positive correlation with tonin expression in both TGM`(rTon) and their respective wild-type littermates. The ACE activity and expression levels of 65-kDa N-domain angiotensin I-converting enzyme isoform were significantly increased in the TGM`(rTon) when compared with WT. ACE2 expression levels were statistically significantly higher in the TGM`(rTon) when compared with WT. Angiotensin 1–7 (Ang(1–7)) and Ang I levels were significantly lower in the TGM`(rTon).

We suggest that the environment of tonin abundance may increase N-domain ACE activity liberated by a secretase able to cleave somatic ACE.

The aim of this study was to assess the antihypertensive efficacy and safety of aliskiren versus ramipril or losartan in hypertensive patients with type 2 diabetes mellitus, microalbuminuria and uncontrolled hypertension, despite the use of optimal conventional antihypertensive therapy.

In this open-label active comparator study, 126 patients were randomly assigned to receive 24 weeks of additional therapy with aliskiren (Group A) or either losartan or ramipril (Group B), according to whether a patient was already treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, respectively.

After 24 weeks, both treatment groups experienced a significant reduction of systolic blood pressure (−11.37% and −8.47%, respectively; both p <0.001 vs. baseline) and diastolic blood pressure levels (−10.67% and −9.28%, respectively; both p <0.001 vs. baseline), with a greater reduction of mean systolic values in Group A compared with Group B (p <0.001). Furthermore, after six months microalbuminuria was significantly decreased in both treatment groups (−67.62% and −49.1%, respectively; both p <0.001), with a reduction rate in Group A significantly higher than in Group B (p<0.001).

The addition of aliskiren to optimal conventional therapy provided a higher reduction of blood pressure and urinary albumin excretion when compared with the addition of losartan or ramipril.

The purpose of this study was to compare the effects of benazepril and losartan on endothelial function and vascular stiffness, in patients with diabetes mellitus and hypertension.

We included hypertensive diabetic patients with an office systolic blood pressure (BP) ⩾ 130 mmHg and/or diastolic BP ⩾ 80 mmHg. Patients were rolled over to amlodipine for 6 weeks, then we performed C-reactive protein assays, BP measurement and vascular tests; next, patients were randomized to benazepril or losartan. The tests were repeated after 12 weeks.

We randomized 14 patients to benazepril and 16 to losartan. There were no differences in systolic (139 versus 134 mmHg, p = 0.618) and diastolic (82 versus 80 mmHg, p = 0.950) BP at the end of the study. C-reactive protein values were lower in the benazepril group (0.38 versus 0.42 mg/dl, p = 0.020). There was a slightly higher flow-mediated vasodilation (FMD) response in the benazepril group (45% increase, p = 0.057) than in the losartan group (19% increase, p = 0.132). Both central systolic BP (129 versus 123 mmHg, p = 0.934) and carotid-femoral pulse wave velocity (cfPWV) (8.5 versus 8.5 m/s, p = 0.280) were the same between groups.

Hypertensive diabetic patients using benazepril had a greater reduction in C-reactive protein, and a slight improvement in FMD, than those taking losartan.

The renin-angiotensin system (RAS) has been considered to play an important role in the regulation of blood pressure. This study aimed to investigate the correlation between RAS gene polymorphisms and essential hypertension (EH) in the Chinese Yi ethnic group.

A total of 244 EH subjects and 185 normotensive individuals from the Chinese Yi ethnic group were genotyped for AGT M235T (rs699), AT1R A1166C (rs5186), ACE I/D (rs4340) and ACE G2350A (rs4343) polymorphisms by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method.

Significant differences in the allele and genotype frequency of ACE G2350A were observed between the EH cases and controls (p=0.001, 0.002). After being grouped by gender, significant differences in the allele and genotype frequency of ACE G2350A and AT1R A1166C were observed between females of the EH cases and controls (ACE G2350A: p=0.000, 0.002; AT1R A1166C: p=0.008, 0.011). After excluding the influence of multifactorial interactions, the ACE G2350A polymorphism is significantly associated with the pathogenesis of EH in the Chinese Yi ethnic group (odds ratio (OR)=1.656, 95% confidence interval (CI) 1.807–2.524, p=0.019).

The RAS-related ACE G2350A polymorphism is associated with the pathogenesis of EH in the Chinese Yi ethnic group.

To clarify the association of angiotensin-converting enzyme (ACE) gene deletion/insertion polymorphism with risk of pregnancy-induced hypertension.

We systematically searched China National Knowledge Infrastructure, Wanfang database, Chongqing WeiPu database and PubMed up to March 2014 to collect related case–control studies. RevMan 5.0 software was used for meta-analysis after evaluating the quality of enrolled studies and extracting the data.

A total of 45 case–control studies was selected, including 10,236 subjects. The meta-analysis was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) after genotype consolidation. In total, D allele vs I allele: OR 1.57, 95% CI 1.33–1.86; genotype DD vs genotype II + DI: OR 1.86, 95% CI 1.48–2.32; genotype II vs genotype DI + DD: OR 0.65, 95% CI 0.53–0.80. In the Asian population, D allele vs I allele: OR 1.80, 95% CI 1.36–2.38; genotype DD vs genotype II + DI: OR 2.25, 95% CI 1.53–3.30; genotype II vs genotype DI + DD: OR 0.56, 95% CI 0.41–0.76. In the Caucasian population, D allele vs. I allele: OR 1.24, 95% CI 1.08–1.44; genotype DD vs. genotype II + DI: OR 1.25, 95% CI 1.10–1.41; genotype II vs. genotype DI + DD: OR 0.96, 95% CI 0.83–1.11.

The ACE gene insertion/deletion polymorphism is associated with the risk of pregnancy-induced hypertension.

The authors tested the hypothesis that combined use of dexmedetomidine on fetal rats during isoflurane exposure in maternal anesthesia can attenuate the abnormal spatial learning and memory abilities in adults via the renin–angiotensin–aldosterone system.

Fifty timed-pregnancy rats were randomly assigned to five groups (Dex+Iso, Sal+Iso, Sal+Oxy, Dex+Oxy, and a control group ) on embryonic day 14 to receive five different dispositions, i.e. combined injection of dexmedetomidine (Dex) or saline (Sal) and inhalation of isoflurane (Iso), oxygen (Oxy), or normal air for 4 h (n = 10).

The latency time(s) from day 1 to day 4 all showed a decreasing tendency in all four groups. The synaptic count of the Sal+Iso group was significantly lower than the Control group (p < 0.05), suggesting that severe neurodegeneration occurred under the influence of fetal isoflurane exposure. In contrast, the synapse count of the Dex+Iso group was near to that of Control group. The rats are protected in neurodevelopmental, normal development.

Combine use of dexmedetomidine during exposure to isoflurane in utero during middle-pregnancy can attenuate the impairment of spatial learning and memory abilities for the rats in adulthood.

Dipeptidyl peptidase (DPP)-4 inhibitors, a novel oral anti-diabetic agents, exert a protective effect on pancreatic β-cell function in patients with type 2 diabetic mellitus (T2DM). However, their beneficial effect in hypertensive T2DM patients treated with angiotensin receptor blockers (ARBs) has not been investigated.

In this open-label multicenter randomized study, a total of 55 hypertensive T2DM patients treated with ARBs were randomly assigned to receive the DPP-4 inhibitor sitagliptin or sulfonylurea (SU).

After 24 weeks of treatment, a significant reduction in fasting blood glucose was only observed in the sitagliptin group, while HbA1c was significantly reduced in both groups. Homeostasis model assessment of insulin resistance was not significantly improved in either group. Indicators of pancreatic β-cell function, including proinsulin to insulin ratio and homeostasis model assessment of β-cell function, were significantly improved in the sitagliptin group, but not in the SU group. The beneficial effects of sitagliptin were observed in hypoglycemic drug naïve patients, but not in patients who had received SU monotherapy prior to the study.

Treatment with the DPP-4 inhibitor sitagliptin might exert beneficial effects on pancreatic β-cell function in ARB-treated T2DM patients and its efficacy might be more pronounced in hypoglycemic drug naïve patients.

Urinary angiotensinogen is considered a reliable biomarker for intrarenal renin–angiotensin system activity. The aims of this study were to assess the urinary angiotensinogen level during the first day of life and to evaluate its correlation with renal function in critically ill neonates.

Urinary angiotensinogen concentration during the first 24 hours of life was measured in 98 critically ill neonates. Neonatal renal function was assessed by urinary levels of cystatin-C, albumin and α₁-microglobulin and urinary electrolyte excretion.

Urinary angiotensinogen level decreased with increasing gestational age and body weight in critically ill neonates (P<0.001). After adjustment for gestational age, urinary angiotensinogen level correlated with urinary fractional excretion of sodium and urinary levels of cystatin-C and α₁-microglobulin. Multivariate linear regression identified a significant impact of urinary cystatin-C on urinary angiotensinogen level (P<0.001). Furthermore, urinary angiotensinogen was significantly increased in neonates with a urinary cystatin-C-to-creatinine ratio ⩾2500 ng/mg, which was the optimal cut-off value to predict acute kidney injury in our previous study.

The urinary angiotensinogen level correlates with the overall maturity of renal function during the early postnatal period in critically ill neonates and an increased urinary angiotensinogen level might reflect renal injury in immature neonates.

Angiotensin-converting enzyme inhibitors (ACEis) improve survival; however, their effect on erythropoiesis remains a matter of debate in this population. Since insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene largely influences serum ACE activity, its effect on erythropoiesis is also anticipated.

In this multicentre, cross-sectional study of 660 patients on maintenance haemodialysis, we analysed the effect of ACEi use and ACE gene I/D polymorphism on haemoglobin levels and erythropoietin resistance. Patients were allocated in groups based on genotype and ACEi therapy. We identified 128 matched pairs with I/I and D/D genotypes.

There was no difference in haemoglobin levels between genotype groups. Haemoglobin levels were lower in patients on ACEi therapy in the entire cohort (95.5±12.1 g/l vs 97.4±13.4 g/l, p=0.02) and patients with I/D (95.2±11 g/l vs 98.2±11.9 g/l, p=0.04) and D/D (93.3±13.2 g/l vs 97.4±14.2 g/l, p=0.02) genotypes. In patient pairs treated with ACEi therapy, subjects with D/D genotype had lower Haemoglobin level (93.0±12.8 g/l vs 98.2±11.9 g/l, p=0.006) and higher erythropoietin resistance index (ERI) (199.1 vs 175.0, p=0.046) than individuals with I/I genotype.

These results indicate that ACEi therapy may increase erythropoietin resistance and worsen erythropoiesis in haemodialysis patients with the D allele.

Kidney development is key to the onset of hypertension and cardiovascular diseases in adults, and in the fetal stage will be impaired by a lack of nutrients in utero in animal models. However, few human studies have been performed.

Kidney samples from fetuses in a fetal growth restriction (FGR) environment were collected and the morphological characteristics were observed. Potentially molecular mechanisms were explored by analyzing apoptosis and kidney-development related gene expression.

The results indicated that no malformations were observed in the kidney samples of the FGR group, but the mean kidney weight and volume were significantly decreased. Moreover, the ratio of apoptotic cells and Bax-positive cells was increased and the ratio of Bcl-2-positive cells was decreased in the FGR group, indicating potential apoptosis induction under an in utero FGR environment. Finally, aberrant expression of renin and angiotensinogen indicated potential kidney functional abnormalities in the FGR group.

Our study suggested increased apoptosis and decreased renin and angiotensinogen expression during human kidney development in an FGR environment. The current results will be helpful to further explore the molecular mechanism of FGR and facilitate future studies of hypertension and cardiovascular diseases and the establishment of preventive methods.

High spontaneous activity of the renin–angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function during hypoglycaemia.

Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps.

Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan was observed.

In conclusion candesartan has no effect on cerebral function during mild experimental hypoglycaemia in subjects with type 1 diabetes and high RAS activity. Candesartan may reduce glucose utilisation or increase endogenous glucose production during hypoglycaemia.

This study aimed to evaluate the protective effects of curcumin on angiotensin-converting enzyme (ACE) gene expression, oxidative stress and anti-oxidant status in thioacetamide (TAA)-induced hepatotoxicity in rats.

Total 32 albino Wistar rats (male, 200–250 g) were divided into six groups (n=8). Group 1: untreated controls; Group 2: received TAA (200 mg/kg body weight (b.w.); i.p.) for 12 weeks; Group 3: received curcumin (75 mg/kg b.w.) for 24 weeks; Group 4: received TAA (200 mg/kg b.w.; i.p.) for 12 weeks+curcumin (75 mg/kg b.w.) for 12 weeks.

A significantly higher ACE gene expression was observed in TAA-induced groups as compared with control, indicating more synthesis of ACE proteins. Treatment with curcumin suppressed ACE expression in TAA liver and reversed the toxicity produced. TAA treatment results in higher lipid peroxidation and lower GSH, SOD and CAT than the normal, and this produces oxidative stress in the liver. Cirrhotic conditions were confirmed by serum enzymes (ALT, AST and ALP) as well as histopathological observations.

Curcumin treatment reduced oxidative stress in animals by scavenging reactive oxygen species, protecting the anti-oxidant enzymes from being denatured and reducing the oxidative stress marker lipid peroxidation. Curcumin treatment restores hepatocytes, damaged by TAA, and protects liver tissue approaching cirrhosis.

Brachial blood pressure increases with exercise and an excessive rise predicts increased cardiovascular risk. Measurement of brachial blood pressure alone may exaggerate the true blood pressure elevation due to exercise-induced change to pressure amplification. Whether blood pressure-lowering treatment modulates pressure amplification during exercise is unknown.

Thirty-two participants with stage 1–2 hypertension (mean age 59.2 years) received eight weeks’ blood pressure lowering with either aliskiren (300mg, n=16) or valsartan (320mg, n=16). Brachial and central aortic pressure (CASP) were measured non-invasively during treadmill exercise (Bruce protocol) at baseline, after eight weeks’ treatment and 48 hours following treatment withdrawal.

The rise in brachial blood pressure with exercise exceeded the rise in CASP, indicative of enhanced pressure amplification. Eight weeks’ treatment elicited similar reductions in brachial blood pressure and CASP which did not differ between rest and peak exercise (p>0.05). The exercise-induced increase in systolic pressure amplification did not differ between baseline and following eight weeks’ treatment (p>0.05). These effects remained unchanged following treatment withdrawal.

Blood pressure lowering does not directly influence the relationship between aortic and brachial pressure either at rest or during exercise in patients with hypertension, other than through proportionate lowering of both pressures. These effects remained unchanged 48 hours after a simulated missed medication dose.

To investigate the effect of telmisartan on the lipometabolisms and the proinflammatory factors secreted from 3T3-L1 adipocytes and to explore the possible mechanisms.

Telmisartan was applied to interfere with mature 3T3-L1 adipocytes. The culture’s free fatty acids, interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) were evaluated. Oil Red O staining was used to determine the adipogenesis of 3T3-L1 adipocytes. ¹⁸F-FDG uptake levels corrected for protein content were determined by cellular radioactivity. The total RNA was isolated for hybridization experimentation in the microarray.

Telmisartan reduced lipid storage and increased ¹⁸F-FDG uptake in a dose-dependent manner, reduced the levels of IL-6 and TNFα and increased those of free fatty acids. One hundred and fifty-seven differentially expressed genes were found by microarray. The mitogen-activated protein kinase (MAPK) signaling pathway involved in the secretion of proinflammatory factor and lipid metabolisms was affected by telmisartan. The expression of endothelial nitric oxide synthetase gene 3 (Nos3) and carnitine palmitoyl transferase 1α (CPT1α) was up-regulated by telmisartan.

Telmisartan affected lipometabolisms and the proinflammatory factors secreted from adipocytes. Nos3, CPT1α and the MAPK pathway being affected by telmisartan may be the underlying cause of the improvement in lipid metabolisms and secretion of proinflammatory factors of differentiated 3T3-L1 adipocytes.

To investigate the effects of the angiotensin-(1-7) signaling pathway and the possible role of atrial natriuretic peptide (ANP) on atrial electrical remodeling in canines with acute atrial tachycardia.

Forty dogs were randomly assigned to eight groups (five dogs/group): sham, paced control, paced + angiotensin-(1-7), paced + angiotensin-(1-7) + Mas inhibitor, paced + angiotensin-(1-7) + Akt inhibitor, paced + angiotensin-(1-7) + PI3K inhibitor, paced + angiotensin-(1-7) + nitric oxide (NO) inhibitor, and paced + angiotensin-(1-7) + A-71915 (ANP receptor antagonist). Rapid atrial pacing was maintained at 600 bpm for 2 h for all groups, except the sham group, and angiotensin-(1-7) (6 μg kg⁻¹ h⁻¹), Mas inhibitor (5.83 μg kg⁻¹ h⁻¹), Akt inhibitor (2.14 μg kg⁻¹ h⁻¹), PI3K inhibitor (2.86 μg kg⁻¹ h⁻¹), NO synthase inhibitor (180 μg kg⁻¹h⁻¹), or A-71915 (0.30 μg kg⁻¹ h⁻¹) were administered intravenously. Atrial effective refractory periods, inducibility, and duration of atrial fibrillation (pacing cycle lengths: 300, 250, and 200 ms), and left atrial ANP concentrations were measured.

After pacing, the atrial effective refractory periods at the six sites shortened with increased inducibility and duration of atrial fibrillation, which was attenuated by angiotensin-(1-7), and increased ANP concentrations, which was promoted by angiotensin-(1-7) (paced control vs. sham; P < 0.05). All inhibitors and A-71915 blocked the electrophysiological effects of angiotensin-(1-7). ANP secretion induced by angiotensin-(1-7) was also blocked by all inhibitors.

Angiotensin-(1-7) prevented acute electrical remodeling in canines with acute atrial tachycardia via the angiotensin-(1-7)/Mas/PI3K/Akt/NO signaling pathway. ANP was related to the anti-arrhythmic effects of angiotensin-(1-7).

We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day).

Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis.

The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects.

Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.

Clinical studies demonstrated the benefits of eplerenone (EPL) in reduction of cardiovascular events in diabetic patients. Since acute myocardial infarction (AMI) and stroke are related to acute intravascular thrombosis, we postulate that the beneficial effects of EPL may result from its antithrombotic action.

Streptozotocin (STZ)-induced diabetic rats were treated with EPL (100 mg/kg/day) for 10 days. Thrombosis in the carotid artery was stimulated electrically.

Thrombosis development was enhanced in STZ-induced diabetic rats as compared to normoglycaemic controls. EPL caused prolongation of the time to artery occlusion, reduction in the incidence of occlusion and decrease in thrombus weight. Changes in the thrombi structure and the inhibition of hypertrophy of the tunica media in the artery wall were also observed. EPL caused reduction in tissue factor, plasminogen activator inhibitor type 1 and interleukin-1β plasma levels.

Our study demonstrated the antithrombotic effect of EPL manifested by a decrease in the dynamics of thrombus formation and changes in its structure. The changes in thrombosis process were accompanied by antihaemostatic, profibrinolytic and anti-inflammatory effects. The aldosterone blockade with EPL seems to be an additional pharmacological strategy for the prevention and treatment of thrombotic disorders in diabetes.

Previous case-control studies on the relation between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and breast cancer did not reach the same conclusion. In the present study, we aimed to further evaluate the relationship between the ACE gene I/D polymorphism and breast cancer.

We selected 13 case-control studies related to ACE gene I/D polymorphism and breast cancer by searching PubMed, EMBase, Chinese Biomedical Literature Database, Chinese CNKI, and Wanfang database. To test the heterogeneity between each study, we utilized the Q-test and I² test. To merge the odds ratio (OR) and 95% confidence interval (CI), we utilized the random effects model during the analyses.

The present study included 1997 patients with breast cancer and 8404 cancer-free control subjects. By meta-analysis, we did not find any association of ACE gene I/D polymorphism with breast cancer in different model (DD vs (ID+II): OR=1.28, 95% CI (0.90–1.81), p=0.16; II vs (ID+DD): OR=0.99, 95% CI (0.81–1.21), p=0.93; D allele vs I allele: OR=1.15, 95% CI (0.94–1.41), p=0.18).

We concluded that ACE gene I/D polymorphism was not associated with breast cancer.

Recently it was shown that the classic renin-angiotensin system (RAS) is locally expressed in small intestinal enterocytes and exerts autocrine control of glucose transport. The aim of this study was to investigate if key components for the Angiotensin III (AngIII) and IV (AngIV) formation enzymes and the AngIV receptor, insulin-regulated aminopeptidase (IRAP), are present in the healthy jejunal mucosa. A second aim was to investigate AngIV effects on glucose-induced mucosal transport in vitro.

Enteroscopy with mucosal biopsy sampling was performed in healthy volunteers. ELISA, Western blotting and immunohistochemistry were used to assess the protein levels and localization. The functional effect of AngIV was examined in Ussing chambers.

The substrate Angiotensin II, the enzymes aminopeptidases-A, B, M as well as IRAP were detected in the jejunal mucosa. Immunohistochemistry localized the enzymes to the apical brush-border membrane whereas IRAP was localized in the subapical cytosolic compartment in the enterocyte. AngIV increased the glucose-induced electrogenic transport in vitro.

The present study indicates the presence of substrates and enzymes necessary for AngIV formation as well as the receptor IRAP in the jejunal mucosa. The functional data suggest that AngIV regulates glucose uptake in the healthy human small intestine.

Primary aldosteronism (PA) represents the most common cause of secondary hypertension. Beyond increased blood pressure, additional harmful effects of aldosterone excess including inappropriate left ventricle (LV) hypertrophy were found. We evaluated the effect of adrenalectomy and spironolactone on blood pressure and myocardial remodelling in a long-term follow-up study.

Thirty-one patients with PA were recruited. Fifteen patients with confirmed aldosterone-producing adenoma underwent adrenalectomy; in the remaining 16 patients, treatment with spironolactone was initiated. Laboratory data, 24-hour ambulatory blood pressure monitoring (ABPM) and echocardiography parameters were evaluated at baseline and at a median follow-up of 64 months.

Both approaches reduced blood pressure (p = 0.001 vs. baseline). In both groups we observed a decrease in end-diastolic (p = 0.04, p = 0.01) and end-systolic LV cavity diameters (p = 0.03, p = 0.01). Interventricular septum and posterior wall thickness reduction was significant only after adrenalectomy (p = 0.01, p = 0.03) as was reduction of LV mass index (p = 0.004). A trend to lower LV mass on spironolactone was caused predominantly by diminution of the LV cavity, which was reflected in increased relative wall thickness (p = 0.05).

Although both surgical and conservative treatment can induce a long-term decrease of blood pressure, adrenalectomy seems to be more effective in reduction of LV mass, as it reverses both wall thickening and enlargement of the LV cavity.

In this study, we investigated the molecule mechanisms of podocyte injury and proteinuria and the protective effects of losartan.

This study set up three groups: a control group; an Ang II group (Ang II 10^–6 mol/l, Sigma); and a losartan group (losartan 10^–6 mol/l, Sigma). We used RT-PCR assay to detect TRPC6 mRNA expression, and Western blot to detect TRPC6 protein expression.

TRPC6 overexpression was the basic change of podocyte injury and proteinuria occurrence. Losartan can treat podocyte injury and proteinuria induced by Ang II via downregulation of TRPC6 in podocytes.

These findings maybe provide an ideal drug target for the diagnosis and treatment of acquired glomerular diseases.

Angiotensin-converting enzyme (ACE) I/D polymorphism has been indicated to be correlated with aortic aneurysm (AA) susceptibility, but study results are still debatable. Thus, a meta-analysis was conducted.

Databases including PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) were searched. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated.

Ten studies with 3557 cases and 5231 controls were included in this meta-analysis. The association between ACE I/D genotype and AA risk was significant (OR=1.30; 95%CI, 1.07–1.57; p<0.01; I²=68%). When stratified by ethnicity, a significantly elevated risk was observed in Caucasians (OR=1.31; 95%CI, 1.07–1.61; p<0.01; I²=71%). In the abdominal AA subgroup, a significantly increased risk was observed (OR=1.29; 95%CI, 1.03–1.62; p=0.02; I²=73%). However, ACE I/D polymorphism was not associated with thoracic AA risk (OR=1.33; 95%CI, 0.85–2.07; p=0.21; I²=52%). Subgroup analysis on blood pressure status showed that an increased risk was found in hypertensive patients (OR=1.52; 95%CI, 1.02–2.26; p=0.04; I²=0%) but not in normotensive subjects (OR=1.46; 95%CI, 0.72–2.96; p=0.30; I²=25%).

In conclusion, this meta-analysis suggested that ACE I/D polymorphism is a risk factor for AA.

Angiotensin-converting enzyme (ACE) and ACE2 are key regulators of the renin–angiotensin system, which has been shown to participate in a series of cardiovascular diseases. We hypothesized that dysregulated gene expression of ACE and ACE2 contribute to the formation of thoracic aortic dissection and aneurysm.

We assessed ACE plasma concentration in 73 patients with acute thoracic aortic dissection (n=34), aneurysm (n=18), coronary heart disease (n=21) and 13 healthy volunteers. ACE and ACE2 gene expression in available aortic tissues was also examined by using quantitative real-time polymerase chain reaction.

In patients with acute aortic dissection, ACE plasma concentration and its mRNA level in aortic tissue were markedly reduced compared with those in patients with aneurysm, coronary heart disease and healthy controls. The level of ACE2 gene expression in dissection samples was also significantly lower than that in aneurysm (8.01±7.44, p<0.01) and coronary heart disease groups (9.61±11.54, p<0.01). A strong correlation was observed between the gene expressions of ACE and those of ACE2, and ACE to ACE2 ratio was significantly elevated in dissection tissues.

Imbalanced down-regulation of ACE and ACE2 mRNA expression levels may play an important role in the development and progression of thoracic aortic aneurysmal dilatation and subsequently dissection.

Isolated nuclei of sheep proximal tubules express angiotensin (Ang) receptors as well as angiotensinogen (AGT) and renin. The present study characterized the NRK-52E tubular epithelial cell line for the intracellular expression of renin-angiotensin system (RAS) components.

RAS components were visualized by immunofluorescent staining in intact cells and protein expression in isolated nuclei.

An antibody to the angiotensin I (Ang I) sequence of AGT (AI-AGT) revealed only cytosolic staining, while an antibody to an internal sequence of AGT (Int-AGT) revealed primarily nuclear staining. Immunoblots of nuclear and cytosolic fractions confirmed the differential cell staining of AGT. Immunostaining for renin was present on nuclei of intact cells. Nuclear renin activity averaged 0.77±0.05 nmol/mg protein/h that was reduced by aliskiren (0.13±0.01 nmol/mg/h, n=3, p<0.01); trypsin activation increased activity three-fold. Peptide staining localized angiotensin II (Ang II) and Ang-(1-7) to the nucleus and peptide content averaged 59±2 and 57±22 fmol/mg (n=4), respectively. Peptide metabolism in isolated nuclei revealed the processing of Ang I to Ang-(1-7) by thimet oligopeptidase.

We conclude that the NRK-52E cells express an intracellular RAS localized to the nucleus and may be an appropriate cell model to elucidate the functional relevance of this system.

The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction.

The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides.

Administration of lisinopril or LisW-S caused a significant decrease in Ang 1–8/Ang 1–10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1–7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1–5/Ang 1–7 ratio. This indicates LisW-S C-domain specificity as Ang 1–5 is generated by hydrolysis of Ang 1–7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP.

LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions.

We aimed to determine the association between plasma aldosterone and renin levels as well as their ratios with carotid plaques in patients with coronary artery disease (CAD).

Carotid intima-media thickness (IMT) and plaque score were evaluated in 111 patients with stable CAD. Plasma renin and aldosterone levels were measured in all patients. Aldosterone to renin ratio (ARR) was calculated. All patients were categorized into: Group 1 (normal coronary angiography), Group 2 (patients had CAD but without carotid plaque) and Group 3 (patients had CAD and at least one carotid plaque).

Renin levels are significantly higher in Group 3 than in Group 1 and 2. ARR was significantly lower in Group 3 than in Group 1 and 2. Renin levels were found to be positively correlated with carotid IMT and plaque score but ARR was inversely associated with carotid IMT and plaque score. Renin levels and ARR are independently associated with presence of carotid plaque in CAD patients (OR 1.124, CI 1.021–1.237, p = 0.017 and OR 0.906, CI 0.839–0.978, p = 0.011, adjusted for age, respectively).

Plasma renin and ARR but not aldosterone are independently associated with presence of carotid plaques in CAD patients. Hence, the linkage between aldosterone and renin plays a more important role than aldosterone alone in carotid atherosclerosis.

Among the genetic factors for coronary artery diseases, PAI-1 4G/5G and ACE I/D polymorphisms can be noted. This study was carried out to investigate the association of these two polymorphisms and their synergism in coronary artery disease (CAD) from a sample of the Iranian population.

Sixty-one patients with a history of CAD and 92 healthy controls participated in our study. After DNA extraction from leukocytes, PCR was performed to characterize PAI-1 4G/5G and ACE I/D polymorphisms, using an amplification refractory mutation system technique.

In the studied patients, PAI-1 polymorphisms were 24.6%, 45.9%, and 29.5% for 4G/4G, 4G/5G and 5G/5G, respectively; the values for controls were 20.7%, 42.2% and 37.0%. The distribution rates of genotypes I/I, I/D and D/D in patients accounted for 29.5%, 45.9% and 24.6%; in the control group these figures were estimated to be 40.2%, 40.2% and 19.6%.

Single and multivariate analyses showed a significant difference for the conventional risk factors, including hypertension, diabetes, hyperlipidemia, smoking and family history, for CAD between patients and controls (p value ≤ 0.001). However, no significant correlation was demonstrated considering ACE and PAI-1 polymorphisms either in association with 4G/4G or D/D genotypes or a combination of them in the Iranian population in the current study.

Preventive medications for dialysis-requiring congestive heart failure (CHF) in non-dialysis Japanese patients with Stage 5 chronic kidney disease (CKD) are unknown. Our aim was to explore which CKD medication was associated with a reduced prevalence of dialysis-requiring CHF in non-dialysis Japanese patients with Stage 5 CKD.

The present multicenter, retrospective, cross-sectional study examined the association between CKD medications and the prevalence of dialysis-requiring CHF in non-dialysis Japanese patients with Stage 5 CKD.

There were 1536 Japanese Stage 5 CKD patients who satisfied our inclusion criteria. We had 309 (20.1%) patients whom had developed dialysis-requiring CHF and 940 patients (60.8%) whom had been using angiotensin-II receptor blockers (ARBs) before initiating dialysis. In our multivariate analysis, only ARB use was significantly associated with a lower risk of CHF (Odds ratio (OR): 0.680, 95% confidence interval (CI): 0.516–0.897; p = 0.0064), of the CKD treatments examined in this study.

We found that ARB use during the pre-dialysis period is associated with a lower prevalence of CHF in the non-dialysis Japanese patients with Stage 5 CKD, suggesting a possible prevention of dialysis-requiring CHF by ARBs, in non-dialysis Japanese patients with Stage 5 CKD.

The aim of this study is to evaluate whether the administration of renin-angiotensin system (RAS) inhibitors, angiotensin-I converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), is associated with treatment outcome in patients with esophageal squamous cell carcinoma.

A total of 141 esophageal squamous cell carcinoma patients receiving esophagectomy were identified, and were divided into two groups: an ACEI/ARB group (n=20), and a non-ACEI/ARB group (n=121). The effect of ACEIs or ARBs on cell proliferation and vascular endothelial growth factor (VEGF) secretion of esophageal squamous cell carcinoma cell lines, CE81T/VGH and TE2, were investigated by 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Enzyme-linked immunosorbent assay (ELISA), respectively.

Use of ACEI/ARB (p=0.032), pathologic T stage (p<0.001), pathologic N stage (p=0.012), tumor stage (p=0.006), and tumor location (p=0.032) were significantly associated with superior overall survival. In multivariate comparison, use of ACEI/ARB (p=0.006), tumor stage (p=0.002), and tumor location (p=0.014) represented the independent prognosticators of superior overall survival. In cell lines, ACEIs/ARBs inhibit cell proliferation and VEGF secretion in a dose-dependent manner.

ACEIs/ARBs administration is independently associated with superior overall survival in patients with esophageal squamous cell carcinoma receiving esophagectomy. Our data support further investigation of the role of RAS inhibitors as a potential therapy in esophageal squamous cell carcinoma.

An ex vivo organotypic retinal explant model was developed to examine retinal survival mechanisms relevant to glaucoma mediated by the renin angiotensin system in the rodent eye.

Eyes from adult Sprague Dawley rats were enucleated immediately post-mortem and used to make four retinal explants per eye. Explants were treated either with irbesartan (10 µM), vehicle or angiotensin II (2 μM) for four days. Retinal ganglion cell density was estimated by βIII tubulin immunohistochemistry. Live imaging of superoxide formation with dihydroethidium (DHE) was performed. Protein expression was determined by Western blotting, and mRNA expression was determined by RT-PCR.

Irbesartan (10 µM) almost doubled ganglion cell survival after four days. Angiotensin II (2 µM) reduced cell survival by 40%. Sholl analysis suggested that irbesartan improved ganglion cell dendritic arborisation compared to control and angiotensin II reduced it. Angiotensin-treated explants showed an intense DHE fluorescence not seen in irbesartan-treated explants. Analysis of protein and mRNA expression determined that the angiotensin II receptor At1R was implicated in modulation of the NADPH-dependent pathway of superoxide generation.

Angiotensin II blockers protect retinal ganglion cells in this model and may be worth further investigation as a neuroprotective treatment in models of eye disease.

Hypertension is a serious risk factor affecting up to 30% of the world’s population with a heritability of more than 30–50%. The aim of this study was to investigate the contribution of the polymorphisms localized in the angiotensinogen (AGT) gene, a main component of the renin–angiotensin–aldosterone system, in inducing the susceptibility to essential hypertension (EH) among isolated populations (Yi and Hani minorities) with low prevalence rate from the remote region of Yunnan in China.

A case-control association study was performed, and all subjects were genotyped for the seven single nucleotide polymorphisms localized in the AGT region by polymerase chain reaction–restriction fragment length polymorphism analysis.

Three polymorphisms, i.e. rs5046, rs5049, and rs2478544, were significantly associated with EH among the Hani minority. The associations, found in the Yi minority, did not reach a conclusive level of statistical significance. The polymorphisms of rs2478544 and rs5046 caused the transformations of exonic splicing enhancer sites and transcription factor binding sites, respectively, in the bioinformatic analyses. The haplotype-rs5046T, rs5049A, rs11568020G, rs3789679C, rs2478544C was susceptible for EH among the Hani minority.

Our findings suggested that the AGT polymorphisms have played a vital role in determining an individual’s susceptibility to EH among the isolated population, which would be helpful for EH management in the remote mountainous region of Yunnan in China.

The present meta-analysis aimed to investigate whether there is an association between SERPINE1 rs1799768 polymorphism and sepsis risk and mortality.

Published reports were searched in PubMed, PubMed Central, Gene, PubChem and Google Scholar. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were assessed in a random-effects model.

The results of the overall meta-analysis indicated that an increased sepsis risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.30; 95% CI 1.08–1.56; p = 0.006). When studies were stratified by ethnicity, no significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk in the Asian group. As for the Caucasian population, overall OR was 1.24 (95% CI 1.02–1.51; p = 0.03). The results of the overall meta-analysis indicated that an increased sepsis mortality risk was evidently associated with SERPINE1 rs1799768 polymorphism (OR = 1.73; 95% CI 1.31–2.28; p < 0.0001). When studies were stratified by ethnicity, significant association was observed between SERPINE1 rs1799768 polymorphism and sepsis risk mortality in the Asian group and the Caucasian population.

In conclusion, the meta-analysis suggests that there are significant associations between SERPINE1 rs1799768 polymorphism and risk of sepsis and sepsis mortality.

Aldosterone can induce changes in the expression or activity of Na⁺/H⁺ exchanger isoform 1 (NHE–1) in vascular smooth muscle cells. We aimed to clarify whether chronic mineralocorticoid receptor activation exerts an effect on the activity of NHE–1 in the aorta of mineralocorticoid-induced hypertensive rats.

Uninephrectomized male Sprague-Dawley rats received subcutaneously 10 mg/week of desoxycorticosterone (DOCA) with or without 20 mg/kg of spironolactone, or vehicle alone (n = 20). After four weeks of treatment, the animals were sacrificed; the aorta was excised for subsequent studies, including histological analysis, RT-PCR, Western blot, measurement of NHE-1 activity and vascular contractility in the presence or absence of the selective NHE-1 inhibitor ethyl-isopropyl amiloride (EIPA).

Chronic DOCA treatment increased the NHE-1 activity, systolic and diastolic blood pressure, and aortic wall thickness. All these effects were prevented by co-treatment with Spironolactone (p < 0.05). Phenylephrine-induced vascular contractility was significantly reduced in the DOCA group when EIPA was added in the media (p < 0.05). No significant differences in NHE-1 mRNA or protein levels were detected between groups.

Chronic DOCA administration induced functional and morphological alterations in the rat aorta that are partially explained by enhanced NHE-1 activity and prevented by spironolactone. However, we did not observe changes in the NHE-1 transcript or protein levels, suggesting that the effect may be due to post-transcriptional modifications induced by mineralocorticoid receptor activation.

Breast cancer is the most common malignancy that is believed to be largely under genetic control. We therefore investigated both individual and interactive associations of six well-characterized polymorphisms in three genes of the renin-angiotensin system with breast cancer among Han Chinese women.

This was a hospital-based study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched controls. There were significant differences in genotype and allele distributions of ACE gene rs4343 (p_gentoype = 0.002 and p_allele < 0.001) and AGTR1 gene rs5186 polymorphisms (p_gentoype < 0.001 and p_allele < 0.001), even with a Bonferroni-corrected alpha of 0.0042 (0.05/12). Allele combinations of T-T-T-G-C-A (alleles in order of rs5050, rs699, rs4291, rs4343, rs188018 and rs5186), G-C-T-G-C-A and T-C-T-G-C-C, respectively, had the age-adjusted odds of 2.21 (p = 0.021), 3.01 (p = 0.021) and 5.24 (p = 0.015) for breast cancer, whereas allele combination T-C-T-A-T-A was associated with a 76% (p = 0.008) reduced risk. Interaction analysis revealed an overall best two-locus model including rs4343 and rs4291 polymorphisms, and this model had the maximal testing accuracy of 0.6259 with a cross-validation consistency of 10 (p = 0.0015).

Our findings support a contributory role of the ACE gene, with its genetic polymorphisms acting synergistically, in predisposition to breast cancer among Han Chinese women.

Some studies have evaluated the associations between the angiotensin-converting enzyme 2 (ACE2) gene polymorphisms and essential hypertension (EH) risk. However, the results remain uncertain. We carried out a meta-analysis to derive a more comprehensive estimation of these associations.

Case-control studies were identified by searching PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wangfang databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations.

Significant associations were found between the ACE2 G8790A polymorphism and EH risk in males (OR = 1.27; 95% CI, 1.11–1.44; p = 0.0004; I² = 34%) and females (OR = 1.21; 95% CI, 1.09–1.34; p = 0.0003; I² = 31%), respectively. Significant associations were also observed between the ACE2 rs2106809 polymorphism and EH risk in males (OR = 1.24; 95% CI, 1.10–1.39; p = 0.0004; I² = 18%) and females (OR = 1.39; 95% CI, 1.27–1.51; p < 0.00001; I² = 0%), respectively. However, there was no significant association between the ACE2 A1075G polymorphism and EH risk in males (OR = 1.27; 95% CI, 0.77–2.10; p = 0.35; I² = 69%) and females (OR = 1.02; 95% CI, 0.83–1.26; p = 0.84; I² = 33%), respectively.

These results suggest that the ACE2 G8790A and rs2106809 polymorphisms may be associated with EH risk.

The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22^phox reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity.

The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment.

Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001.

These data added to our previous results further provide a mechanistic rationale for olmesartan’s antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials.

The association of ACE I/D polymorphism and hemodynamic response to exercise have been limited to primarily aerobic exercises. We hypothesized that D allele carriers would show greater hemodynamic response to resistance exercise, as has been observed with aerobic. This study aimed to investigate the association of ACE I/D polymorphism and hemodynamic (blood pressure (BP), heart rate (HR) and rate-pressure product (RPP)) response to resistance exercise in young healthy subjects.

ACE I/D polymorphisms were studied by PCR analysis from 75 healthy men. Subjects completed a resistance exercise session of three sets of 10 knee extension repetitions with loads of 50, 75 and 100% of 10RM and two-minute rest intervals. Hemodynamic measures were recorded before and immediately after each set. Analysis of variance was used to identify significant differences among ACE genotypes.

ACE I/D polymorphism is associated with hemodynamic response to resistance exercise, as healthy subjects with ACE D allele were prone to higher responses. In addition, this phenotypic difference seems to be a load-dependent trend.

ACE DD carriers exhibit greater heart work during resistance exercise. Future studies should focus on the influence of resistance training period with different workloads on the hemodynamic response in healthy individuals with different ACE genotypes.

The objective of this article is to investigate the effect of renin-angiotensin system inhibitors (RASIs) on intact parathyroid hormone (iPTH) levels in continuous ambulatory peritoneal dialysis (CAPD) patients.

All patients were divided into RASI-treated and non-treated groups. The relationships between the iPTH levels in CAPD patients and the clinical parameters and medication use were analyzed via linear regression.

A total of 149 CAPD patients were included in this study. The average iPTH level of the entire group was 189.4 pg/ml (range, 102.8–373.4 pg/ml). There were 79 (53.0%) and 70 (47.0%) cases in the RASI-treated and non-treated groups, respectively, with average iPTH levels of 139.0 pg/ml (range, 91.6–258.4 pg/ml) and 253.0 pg/ml (range, 134.3–467.2 pg/ml), respectively; this difference was statistically significant (p = 0.001). Multilinear regression analysis showed that age, dialysis vintage, serum phosphatemia, ALP, Hb and RASI use were independent factors that were associated with iPTH level.

RASI use may be associated with a lower iPTH level in CAPD patients, although the underlying mechanism requires further study.

the objective of this article is to evaluate the role of siRNA-silenced TRPC6 on podocyte autophagy and apoptosis induced by AngII.

mouse podocyte cell lines were cultured in vitro. The apoptosis rates of each group were detected using flow cytometry. The expression of LC3-II protein and changes in distribution were detected by confocal laser, and the western blot protocol was employed for detection of protein expression of LC3-II.

AngII-injured podocyte had a significant increase in apoptosis, while silencing TRPC6 could decrease the apoptosis induced by AngII. Autophagy remarkably increased after AngII injury. While silencing TRPC6 stabilized the autophagy expression, AngII could activate the autophagy of podocyte. Autophagy-associated protein LC3-II expression increased after AngII injury. The LC3-II mRNA and the protein level could be down regulated by 3-MA. The silencing of TRPC6 could stabilize the autophagy expression.

the data suggest that AngII can lead to podocyte injury. Autophagy may have beneficial effects in preventing the progression of proteinuria. This study provides some new clues for further exploring the occurrence of podocyte injury and the development mechanism of proteinuria.

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α₂-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigated whether dexmedetomidine induces cardioprotection against myocardial apoptosis injury.

In order to assess the role of dexmedetomidine on myocardial apoptosis, we established a grave scalding rat model. Blood and myocardial tissue from the ventriculus sinister were harvested, then troponin, myocardial apoptosis, and expression of caspase-12, GRP78, and CHOP were assessed.

Dexmedetomidine significantly reduced myocardial apoptosis, improved functional recovery, and reversed myocardial injury induced by grave scalding. The heart rate in the five groups studied was significantly different (p < 0.05). The number of buffy-stained nucleoli in the myocardial cell was highest in the simple scald group. The expression of caspase-12 obviously increased in the simple scald group. The expression of GRP78 and CHOP increased in the simple scald and scald and 50 μg/kg dexmedetomidine groups (p < 0.05).

The results show that dexmedetomidine (DEX) produces cardioprotection against myocardial apoptosis injury. DEX is not only a useful sedative, but also plays a pivotal role in anesthetic cardioprotection. The potential benefits of DEX protection in high risk cardiovascular patients undergoing surgery are enormous.

Angiotensin I converting enzyme (ACE) insertion and deletion (I/D) polymorphism has been implicated in the pathogenesis of osteoarthritis (OA). In recent years, numerous genetic factors have been identified and implicated in OA. In this Asian Indian population-based study, we aimed to evaluate the relationship between ACE (I28005D) gene polymorphism and primary OA. We performed a case-control association study to identify and explore the correlation between clinically, radiologically diagnosed individuals with primary knee OA and the ACE I/D polymorphism.

Genomic DNA was isolated from 200 samples, including 100 OA cases and 100 healthy volunteers. DNA was amplified by polymerase chain reaction (PCR) using I and D allele-specific primers. PCR products were assessed via UV visualization of products electrophoresed on 2% agarose gels.

The groups differed significantly in genotype distributions (p < 0.05). The primary knee OA group showed a considerably higher incidence of the DD genotype and the D allele compared to the control group (OR = 2.14, 95% CI: 1.10–4.15, p = 0.02 and OR = 2.08, 95% CI: 1.39–3.10, p = 0.0003).

The ACE gene polymorphism I28005D was found to be associated with primary knee OA in Asian Indian populations. This is the first study in India to report that the ACE gene polymorphism is a risk factor for early onset primary knee OA.

MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular function including regulation of cardiac hypertrophy, heart failure and blood pressure possibly through AT₁R signalling. However, the miR-132/212 targets in the heart remain unknown.

To understand the role of these miRNAs in cardiac signalling networks, we undertook comprehensive in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts.

MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors, signalling molecules and transcription factors. Subsequent comprehensive in silico analysis identified 24 target genes, of which 22 genes were qPCR validated. We identified seven genes involved in AngII signalling pathways.

We here report novel insight of an extensive network of molecular pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function.

The gene encoding angiotensin-converting enzyme (ACE) has been implicated in the development of several malignancies. We aimed to meta-analyze the association of ACE gene insertion/deletion (I/D) polymorphism with digestive cancer risk and seek possible sources of between-study heterogeneity.

Two authors independently assessed eligibility of each retrieved publication and gathered relevant data. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (CI).

Sixteen publications were qualified for analysis, involving 2903 digestive cancer cases and 10,833 controls. Overall analyses failed to show any significance for digestive cancer risk. There was moderate heterogeneity and lower publication bias for overall comparisons. In subgroup analyses, ACE gene II genotype was associated with a 15% reduced risk (OR=0.85, 95% CI: 0.57–1.27, p=0.434) for gastric cancer, but a 16% increased risk (OR=1.16, 95% CI: 0.89–1.52, p=0.273) for colorectal cancer. By source of controls, the I allele appeared to be a protective factor against digestive cancer in population-based studies (OR=0.87, 95% CI: 0.75–1.00, p=0.055) but a risk-conferring factor in hospital-based studies (OR=1.17, 95% CI: 1.01–1.35, p=0.033).

Our findings suggested that ACE gene I allele might be a protective factor against gastric cancer, necessitating further confirmation in large, population-based studies.

With the development of genome-wide association studies (GWAS) concerning hypertension, a growing number of susceptibility genes related to hypertension have been revealed. Subsequently, several studies have investigated the association between CYP17A1 rs1004467 heritable variation and hypertension; however, the results have been inconsistent. In this study, a meta-analysis was performed to assess the association between the CYP17A1 rs1004467 polymorphism and hypertension risk.

The PubMed, ISI Web of Science and Embase databases as well as China Wanfang, Weipu and the Chinese Journal Full-text Database were used to retrieve all publications from 2005 to 2013 related to case-control studies that reported a link between the risk factors for hypertension and the CYP17A1 polymorphism. All association studies were identified, and a meta-analysis was conducted using the RevMan 5.0 estimate for odds ratios (ORs) to determine whether the A allele predicts hypertension outcomes.

Three articles including five studies (totaling 4495 patients and 3529 controls) were identified. The overall effect suggested that rs1004467 was significantly associated with hypertension (OR=1.22, 95%CI 1.08–1.38, p=0.001).

The present meta-analysis confirmed the significant association between a polymorphism of the CYP17A1 gene and hypertension susceptibility. The CYP17A1 A allele should be considered a risk factor for hypertension.

Incidences of hypertension are increasing and this condition is more common in men than in women. We selected six well-characterized polymorphisms from three X-linked genes (ACE2, AGTR2, apelin) aiming to investigate their interactive association with hypertension among northeastern Han Chinese.

This was a case-control study involving 1009 hypertensive patients and 756 normotensive controls. All polymorphisms except rs3761581 in the apelin gene satisfied the Hardy-Weinberg equilibrium in females. The genotype and allele distributions of rs1403543 in the AGTR2 gene and rs56204867 in the apelin gene differed significantly between patients and controls for both genders, even after the Bonferroni correction (P<0.05/6). The risk prediction was significant for rs1403543 and rs56204867 under both additive and dominant models for both genders. In haplotype analysis, significance was seen for haplotype G-T-G-G-A (alleles in order of rs1978124, rs2106809, rs1403543, rs5194 and rs56204867), which was overrepresented in patients (5.15% versus 1.10% in controls, P_Sim=0.004). Interaction analysis indicated that all derived multifactor dimensionality reduction (MDR) models were non-significant for both genders.

Our findings demonstrate that genetic defects in AGTR2 and apelin genes by themselves may play an independent leading role in determining susceptibility to hypertension in both genders.

Tacrolimus is frequently used as immunosuppressive agent in organ transplantation but its clinical use is limited due to its marked nephrotoxicity.

Male Wistar albino rats weighing 150–200 g (10–12 weeks old) were used. Animals were divided into four groups. Group 1 served as control group and received normal saline, group 2 served as toxic group and received 2 mg/kg tacrolimus i.p., group 3 served as treatment group and received 2 mg/kg tacrolimus i.p. followed by 2 mg/kg aliskiren orally and group 4 served as drug per se group and received 2 mg/kg aliskiren orally. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically.

Treatment with aliskiren decreased the tacrolimus-induced changes in biochemical markers of nephrotoxicity such as blood urea nitrogen and creatinine. Aliskiren also attenuated the effects of tacrolimus on oxidative stress parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that aliskiren attenuated tacrolimus-induced renal damage.

These results suggest that aliskiren has protective effects against tacrolimus-induced nephrotoxicity; implying that renin inhibitor may counteract nephrotic syndrome associated with immunosuppressant use.

Insertion/deletion (I/D) polymorphisms found in the angiotensin converting enzyme (ACE) gene have been associated with hypertension, diabetes and renal disease. The present study sought to determine the association of I/D polymorphisms of the ACE gene with end-stage renal disease (ESRD) patients in Malaysia.

A total of 380 subjects were recruited to determine the genotypes of I/D polymorphisms of the ACE gene. Genotyping was performed using a PCR method. Statistical analyses were carried out using statistical software, and a level of p < 0.05 was considered statistically significant.

The frequencies for II, ID and DD genotypes of the ACE gene were 24.7%, 65.80% and 9.47%, respectively, in ESRD patients, and in control subjects were 45.26%, 47.37% and 7.37% respectively. The frequency for the D allele was found to be higher (42.40%) in ESRD patients compared to control subjects (31.05%). The genotypic and allelic frequencies of I/D polymorphisms of the ACE gene differed significantly (p < 0.05) between ESRD patients and control subjects in the Malaysian population.

The findings of this study indicate that I/D polymorphisms of the ACE gene are a useful marker and are likely to play a major role in determining genetic susceptibility to ESRD in the Malaysian population.