Changes of gene expression profiles in macrophages stimulated by angiotensin II — Angiotensin II induces MCP-2 through AT1-receptor

Abstract

Introduction. Macrophages play critical roles in the development of atherosclerosis and diabetic nephropathy as well as many inflammatory diseases. Angiotensin II type 1 receptor antagonists (AIIA) are beneficial for the prevention of atherosclerosis and diabetic nephropathy suggesting that angiotensin II (Ang II) promotes the development of these diseases. It has recently been reported that Ang II exerts proinflammatory actions in vivo and in vitro. This study was aimed to clarify the direct effects of Ang II on monocytes/macrophages.

Materials and methods. PMA-treated THP-1 cells, a human monocytic leukaemia cell line, were treated with Ang II (10-6 mol/L) for 24 hours with or without AIIA (CV11974). We evaluated gene expression profiles of these cells using DNA microarray system and quantified them by real-time RT-PCR.

Results. DNA microarray revealed that in total 19 genes, including monocyte chemoattractant protein (MCP)-2, were up-regulated by Ang II and down-regulated by AIIA. Real-tim D e RT-PCR showed that up-regulation of MCP-2 with Ang II is blocked by the AIIA (CV11974) but not by an AT₂-receptor antagonist.

Conclusions. These results suggest that Ang II directly stimulates MCP-2 expression through AT1-receptors in activated macrophages.Ang II may contribute to the persistence or amplification of microinflammation in vessel walls, heart and kidney.Vasculoprotective or renoprotective effects of AIIA might partly depend on direct antiinflammatory effects on macrophages.

Keywords

angiotensin II MCP-2 macrophage chemokine candesartan renin-angiotensin system THP-1 DNA array

Get full access to this article

View all access options for this article.

References

Hernandez-Presa M. , Bustos C. , Ortego M. et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factorkappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 1997 ;95:1532-41.

Hirata K. , Shikata K. , Matsuda M. et al. Increased expression of selectins in kidneys of patients with diabetic nephropathy, Diabetologia 1998;41:185-92.

Sugimoto H. , Shikata K. , Hirata K. et al. Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation. Diabetes 1997;46:2075-81.

Okada S. , Shikata K. , Matsuda M. et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes 2003;52:2586-93.

Usui H. , Shikata K. , Matsuda M. et al. MG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant 2003;18:265-72.

Dzau VJ Vascular renin-angiotensin system and vascular protection. J Cardiovasc Pharmacol 1993;22(suppl 5):S1-S9.

Diet F. , Pratt RE , Berry GJ , Momose , Gibbons GH , Dzau VJ Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 1996;94:2756-67.

Chen XL , Tummala PE , Olbrych MT , Alexander RW , Medford RM Angiotensin II induces monocyte chemoattractant protein P -1 gene expression in rat vascular smooth muscle cells. Circ Res 1998;83:952-9.

Potter DD , Sobey CG , Tompkins PK , Rossen JD , Heistad DD Evidence that macrophages in atherosclerotic lesions contain angiotensin II . Circulation 1998;98:800-07.

10.

Iwai N. , Inagami T. , Ohmichi N. , Kinoshita M. Renin is expressed in rat macrophage/monocyte cells. Hypertension 1996;27:399-403.

11.

Okamura A. , Rakugi H. , Ohishi M. et al. Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages. J Hypertens 1999 ;17:537-45.

12.

Yanagitani Y. , Rakugi H. , Okamura A. et al. Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. Hypertension 1999;33:335-9.

13.

Kato S. , Luyckx VA , Ots M. et al. Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney Int 1999;56:1037-48.

14.

Mezzano S. , Droguett A. , Burgos ME et al. Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy. Kidney Int Suppl 2003;86:S64-S70.

15.

Ramakrishnan R. , Dorris D. , Lublinsky A. et al. An assessment of Motorola CodeLink microarray performance for gene expression profiling applications. Nucleic Acids Res 2002;30:e30.

16.

Amann B. , Tinzmann R. , Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1 . Diabetes Care 2003;26:2421-5.

17.

Goodfriend TL , Elliott ME , Catt KJ Angiotensin receptors and their antagonists . N Engl J Med 1996;334:1649-54.

18.

Ardaillou R. Angiotensin II receptors. J Am Soc Nephrol 1999;10(suppl 11):S30-39.

19.

Carey RM , Wang ZQ , Siragy HM Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000;35:155-63.

20.

Stoll M. , Steckelings UM , Paul M. , Bottari SP , Metzger R. , Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 1995:95:651-7.

21.

Kuizinga MC , Smits JF , Arends JW , Daemen M. AT2 receptor blockade reduces cardiac interstitial cell DNA synthesis and cardiac function after rat myocardial infarction. J Mol Cell Cardiol 1998;30:425-34.

22.

Maric C. , Aldred GP , Harris PJ , Alcorn D. Angiotensin II inhibits growth of cultured embryonic renomedullary interstitial cells through the AT2 receptor. Kidney Int 1998;53:92-9.

23.

Yamada T. , Horiuchi M. , Dzau VJ Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA 1996;93:156-60.

24.

Hines J. , Fluharty SJ , Yee DK Chimeric AT1/AT2 receptors reveal functional similarities despite key amino acid dissimilarities in the domains mediating agonist-dependent activation . Biochemistry 2001;40:11251-60.

25.

Esteban V. , Lorenzo O. , Ruperez M. et al. Ruiz-Ortega, Angiotensin II, via AT1 and AT2 receptors and NF-kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction . J Am Soc Nephrol 2004;15:1514-29.

26.

Decock B. , Conings R. , Lenaerts JP , Billiau A. , Van Damme J. Identification of the monocyte chemotactic protein from human osteosarcoma cells and monocytes: detection of a novel N-terminally processed form. Biochem Biophys Res Commun 1990;167:904-09.

27.

Gong X. , Gong W. , Kuhns DB et al. Monocyte chemotactic protein-2 (MCP-2) uses CCR1 and CCR2B as its functional receptor. J Biol Chem 1997;272:11682-5.

28.

Ruffing N. , Sullivan N. , Sharmeen L. , Sodroski J. , Wu L. CCR5 has an expanded ligand-binding repertoire and is the primary receptor used by MCP-2 on activated T cells. Cell Immunol 1998;189:160-8.

29.

Taub DD , Proost P. , Murphy WJ et al. Monocyte chemotactic protein-1 (MCP-1), -2, and -3 are chemotactic for human T lymphocytes. J Clin Invest 1995 ;95:1370-6.

30.

Uguccioni M. , D'Apuzzo M. , Loetscher M. , Dewald B. , M. Baggiolini. Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes . Eur J Immunol 1995 ;25:64-8.

31.

Weber M. , Uguccioni M. , Ochensberger B. , Baggiolini M. , Clark-Lewis I. , Dahinden CA Monocyte chemotactic protein MCP-2 activates human basophil and eosinophil leukocytes similar to MCP-3. J Immunol 1995 ;154:4166-72.

32.

Noso N. , Proost P. , Van Damme J. , Schroder JM Human monocyte chemotactic proteins-2 and 3 (MCP-2 and MCP-3) attract human eosinophils and desensitise the chemotactic responses towards RANTES . Biochem Biophys Res Commun 1994;200:1470-6.