Exercise rescued chronic kidney disease by attenuating cardiac hypertrophy through the cardiotrophin-1 → LIFR/gp 130 → JAK/STAT3 pathway

Abstract

Background

Chronic kidney disease (CKD) is usually associated with cardiac apoptosis and/or cardiac hypertrophy. We hypothesized that exercise can reduce the CKD-induced cardiac damage.

Methods and results

The doxorubicin-induced CKD (DRCKD) model was used in rats to compare two exercise models: 60-min running and 60-min swimming. Results indicated that in healthy normal groups, the signals cardiotrophin-1 (CT-1), interleukin 6 (IL-6), leukaemia inhibitory factor receptor (LIFR), and gp130 were upregulated and janus kinase (JAK) and signal transducer and activation of transcription (STAT) were downregulated by both exercises. In contrast, all signals were highly upregulated in CKD. After exercise training, all signals (CT-1, IL-6, LIFR, gp130, and STAT) were downregulated, with JAK being only slightly upregulated in the running group but not in the swimming group. The myocyte death pathway (CT-1/IL-6 → LIFR/gp130 → PI3K → Akt → Bad) was excluded due to no change found for Bad. Nitric oxide (NO; normal, 15.63 ± 0.86 µmol/l) was significantly suppressed in CKD rats (2.95 ± 0.32 µmol/l), and both running and swimming training highly upregulated the NO level to 30.33 ± 1.03 µmol/l and 27.82 ± 2.47 µmol/l in normal subjects and 24.0 ± 3.2 µmol/l and 22.69 ± 3.79 µmol/l in the DRCKD rats, respectively. The endothelial progenic cells CD34 were significantly suppressed in DRCKD rats, which were not rescued significantly by exercise. In contrast, the CD 34 cells were only slightly suppressed in the healthy subjects by exercise.

Conclusion

Both exercise regimens were beneficial by rescuing cardiac function in CKD victims. Its action mechanism was by way of inhibiting myocyte death and rescuing cardiac hypertrophy.

Keywords

Cardiac hypertrophy chronic kidney disease (CKD)doxorubicin

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References

Manjunath

Tighiouart

Ibrahim

. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003; 41: 47–55.

Napoli

Casamassimi

Crudele

. Kidney and heart interactions during cardiorenal syndrome: a molecular and clinical pathogenic framework. Future Cardiol 2011; 7: 485–497.

Parfrey

. Cardiac disease in dialysis patients: diagnosis, burden of disease prognosis, risk factors and management. Nephrol Dial Transplant 2000; 15: 58–68.

Culleton

Larson

Wilson

. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999; 56: 2214–2219.

Miranda Sde

Macedo

Silva Júnior

. Cardio-renal syndrome: pathophysiology and treatment. Rev Assoc Med Bras 2009; 55: 89–94.

Levin

Thompson

Ethier

. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999; 34: 125–134.

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classiﬁcation, and stratiﬁcation. Am J Kidney Dis 2002; 39: S1–S266.

Mangione

Dal Canton

. Chronic kidney disease epidemic: myth and reality. Intern Emerg Med 2011Suppl 1): 69–76.

Tremblay L. Heart attack and chronic kidney disease. New York: About.com, Heart Health Center. Available at: http://heartdisease.about.com/lw/Health-Medicine/Conditions-and-diseases/Heart-Attack-and-Chronic-Kidney-Disease.htm (2008, assessed 5 June 2012).

10.

Shastri

Sarnak

. Cardiovascular disease and CKD: core curriculum 2010. Am J Kidney Dis 2010; 56: 399–417.

11.

Bongartz

Cramer

Doevendans

. The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 2005; 26: 11–17.

12.

El Desoky

. Drug therapy of heart failure: an immunologic view. Am J Ther 2011; 18: 416–425.

13.

Prabhu

Chandrasekar

Murray

. beta-Adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation 2000; 101: 2103–2109.

14.

Dhingra

Sharma

Arora

. IL-10 attenuates TNF-alpha-induced NF kappaB pathway activation and cardiomyocyte apoptosis. Cardiovasc Res 2009; 82: 59–66.

15.

Engel

Peshock

Armstong

. Cardiac myocyte apoptosis provokes adverse cardiac remodeling in transgenic mice with targeted TNF overexpression. Am J Physiol Heart Circ Physiol 2004; 287: H1303–H1311.

16.

Haudek

Taffet

Schneider

. TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest 2007; 117: 2692–2701.

17.

Kaur

Sharma

Dhingra

. Interplay of TNF-alpha and IL-10 in regulating oxidative stress in isolated adult cardiac myocytes. J Mol Cell Cardiol 2006; 41: 1023–1030.

18.

Kim

Morgan

Choksi

. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell 2007; 26: 675–687.

19.

Kaur

Dhaunsi

Turner

. Interleukin-1 and nitric oxide increase NADPH oxidase activity in human coronary artery smooth muscle cells. Med Princ Pract 2004; 13: 26–29.

20.

Mullens

Abrahams

Francis

. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53: 589–596.

21.

Damman

Voors

Hillege

. CIBIS-2 Investigators and Committees. Congestion in chronic systolic heart failure is related to renal dysfunction and increased mortality. Eur J Heart Fail 2010; 12: 974–982.

22.

Onat

Jelic

Schmidt

. Vascular endothelial sampling and analysis of gene transcripts: a new quantitative approach to monitor vascular inflammation. J Appl Physiol 2007; 103: 1873–1878.

23.

Colombo

Banchs

Celaj

. Endothelial cell activation in patients with decompensated heart failure. Circulation 2005; 111: 58–62.

24.

Jougasaki

. Cardiotrophin-1 in cardiovascular regulation. Adv Clin Chem 2010; 52: 41–76.

25.

Calabrò

Limongelli

Rieglewr

. Novel insights into the role of cardiotrophin-1 in cardiovascular diseases. J Mol Cell Cardiol 2009; 46: 142–148.

26.

Pemberton

Raudsepp

Yandle

. Plasma cardiotrophin-1 is elevated in human hypertension and stimulated by ventricular stretch. Cardiovasc Res 2005; 68: 109–117.

27.

Lopez

Gonzalez

Lasarte

. Is plasma cardiotrophin-1 a marker of hypertensive heart disease? J Hypertens 2005; 23: 625–632.

28.

Cottone

Nardi

Mulè

. Association between biomarkers of inflammation and left ventricular hypertrophy in moderate chronic kidney disease. Clin Nephrol 2007; 67: 209–216.

29.

Talwar

Squire

Downie

. Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction. Clin Sci (Lond) 2000; 99: 83–88.

30.

Jougasaki

. Cardiotrophin-1 in cardiovascular regulation. Adv Clin Chem 2010; 52: 41–76.

31.

Lee

Harris

. Adriamycin nephropathy: a model of focal segmental glomerulosclerosis. Nephrology (Carlton) 2011; 16: 30–38.

32.

Peng

Chen

. Treadmill exercise improved adriamycin-induced nephropathy. J Biol Regul Homeost Agents 2012; 26: 15–28.

33.

Mettler

Young

Ward

. Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats. Cancer Res 1977; 37: 2705–2713.

34.

Szymanski

de Boer

Navis

. Animal models of cardiorenal syndrome: a review. Heart Fail Rev 2012; 17: 411–420.

35.

Noiri E, Nagano N, Negishi K, Doi K, Miyata S, Abe M, et al. Efficacy of darbepoetin in doxorubicin-induced cardiorenal injury in rats. Nephron Exp Nephrol 2006; 104: e6–e14.

36.

Canadian Institute for Health. Information; dialysis and renal transplantation 2001; Vol. 1. Ottawa, Canada: Canadian Organ Replacement Register.

37.

Sarnak

Levey

. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000; 35: S117–S131.

38.

Painter

. Exercise in chronic disease: physiological research needed. Exerc Sport Sci Rev 2008; 36: 83–90.

39.

Bloomfield SA and Coyle EF. Bed rest, detraining, and retention of training-induced adaptations: a review. In: American Collage of Sports Medicine (eds) Resource manual for guidelines for exercise testing and prescription. 2nd edn. Philadelphia: Lea and Febiger, 1993. pp. 115–128.

40.

Miller

Balady

Fletcher

. Exercise and its role in the prevention and rehabilitation of cardiovascular disease. Ann Behav Med 1997; 19: 220–229.

41.

Stevens

Coresh

Greene

. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006; 354: 2473–2483.

42.

National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. New York: NKF. Available at: www.kidney.org/professionals/kdoqi/guidelines_ckd/toc.htm (2002, consulted August 2010).

43.

Liang

. Expression of JAKs/STATs pathway molecules in rat model of rapid focal segmental glomerulosclerosis. Pediatr Nephrol 2009; 24: 1667–1671.

44.

Adams

Vaziri

. Skeletal muscle dysfunction in chronic renal failure: effects of exercise. Am J Physiol Renal Physiol 2006; 290: F753–F761.

45.

Hirschberg

Kopple

. Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats. J Clin Invest 1989; 83: 326–330.

46.

Husain

. Physical conditioning modulates rat cardiac vascular endothelial growth factor gene expression in nitric oxide-deficient hypertension. Biochem Biophys Res Commun 2004; 320: 1169–1174.

47.

Barouch

Cappola

Harrison

. Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice. J Mol Cell Cardiol 2003; 35: 637–644.

48.

Varghese

Harrison

Lofthouse

. beta(3)-Adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. J Clin Invest 2000; 106: 697–703.

49.

Murad

. The role of nitric oxide in modulating guanylyl cyclase. Neurotransmission 1994; 10: 1–4.

50.

d'Ischia

Palumbo

Buzzo

. Interactions of nitric oxide with lipid peroxidation products under aerobic conditions: inhibitory effects on the formation of malondialdehyde and related thiobarbituric acid-reactive substances. Nitric Oxide 2000; 4: 4–14.

51.

Peng

Chen

Hsieh

. Swimming exercise prevents fibrogenesis in chronic kidney disease by inhibiting the myofibroblast transdifferentiation. PLoS One 2012; 7(6): e37388–e37388.

52.

Pennica

King

Shaw

. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci USA 1995; 92: 1142–1146.

53.

Stephanou

Brar

Heads

. Cardiotrophin-1 induces heat shock protein accumulation in cultured cardiac cells and protects them from stressful stimuli. J Mol Cell Cardiol 1998; 30: 849–855.

54.

Wollert

Taga

Saito

. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways. J Biol Chem 1996; 271: 9535–9545.

55.

Freed

Chilton

. Role of myosin light chain kinase in cardiotrophin-1-induced cardiac myofibroblast cell migration. Am J Physiol Heart Circ Physiol 2011; 301: H514–H522.

56.

Zolk

Engmann

Münzel

. Chronic cardiotrophin-1 stimulation impairs contractile function in reconstituted heart tissue. Am J Physiol Endocrinol Metab 2005; 288: E1214–E1221.

57.

Tsutamoto

Asai

Tanaka

. Plasma level of cardiotrophin-1 as a prognostic predictor in patients with chronic heart failure. Eur J Heart Fail 2007; 9: 1032–1037.

58.

Adams

Zhan

Haddad

. Voluntary exercise during chronic renal failure in rats. Med Sci Sports Exerc 2005; 37: 557–562.

59.

Freed

Cunnington

Dangerfield

. Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infracted heart. Cardiovasc Res 2005; 65: 782–792.

60.

Matsui

Fujio

Kunisada

. Leukemia inhibitory factor induces a hypertrophic response mediated by gp130 in murine cardiac myocytes. Res Commun Mol Pathol Pharmacol 1996; 93: 149–162.

61.

Kunisada

Tone

Fujio

. Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation 1998; 98: 346–352.

62.

Latchman

. Cardiotrophin-1: a novel cytokine and its effects in the heart and other tissues. Pharmacol Ther 2000; 85: 29–37.

63.

Wagner

Siddiqui

. Signaling networks regulating cardiac myocyte survival and death. Curr Opin Investig Drugs 2009; 10: 928–937.

64.

Kunisada

Negoro

Tone

. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA 2000; 97: 315–319.

65.

Takahashi

Saito

Kuwahara

. Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. J Mol Cell Cardiol 2005; 38: 185–192.

66.

McMullen

Shioi

Zhang

. Phosphoinositide 3-kinase (p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 2003; 100: 12355–12360.

67.

DeBosch

Treskov

Lupu

. Akt1 is required for physiological cardiac growth. Circulation 2006; 113: 2097–2104.

68.

Rakusan

Microcirculation in the stressed heart. In: Legato

(eds). The stressed heart, Boston, Dordrecht, and Lancaster: Martinus Nijhoff Publ, 1987, pp. 107–123.

69.

Rakobowchuk

Harris

Taylor

. Heavy and moderate interval exercise training alters low-flow-mediated constriction but does not increase circulating progenitor cells in healthy humans. Exp Physiol 2012; 97: 375–385.

70.

Luk

Dai

Siu

. Effect of exercise training on vascular endothelial function in patients with stable coronary artery disease: a randomized controlled trial. Eur J Cardiovasc Prev Rehabil 2012; 19: 830–839.

71.

Frenzel

Schwartzkopff

Höltermann

. Regression of cardiac hypertrophy: morphometric and biochemical studies in rat heart after swimming training. J Mol Cell Cardiol 1988; 20: 737–751.

72.

Van Craenenbroeck

Hoymans

Beckers

. Exercise training improves function of circulating angiogenic cells in patients with chronic heart failure. Basic Res Cardiol 2010; 105: 665–676.

73.

Nikol

Kuhlmann

. Mobilization of stem cells in cardiovascular disease. Improvement of vascularization, cardiac function and arrhythmias. Med Klin (Munich) 2006; 101: 190–192.

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