Korean Circ J.  2007 Mar;37(3):91-96. 10.4070/kcj.2007.37.3.91.

Overview of the Renin-Angiotensin System

• Ryu WS
• Kim SW
• Kim CJ

• KMID: 2227078
• DOI: http://doi.org/10.4070/kcj.2007.37.3.91

Abstract

Angiotensin II is an octapeptide hormone of the renin-angiotensin system (RAS), and it regulates a wide variety of physiological responses including salt and water balance, the blood pressure and the vascular tone. Clinical trials with angiotensin-converting enzyme (ACE) inhibitors have demonstrated survival benefits in subjects with congestive heart failure and myocardial infarction, and this support the importance of angiotensin II in the pathogenesis of cardiovascular diseases. Through activation of small G proteins such as Ras, Rho, and Rac, angiotensin II induces remodeling of vascular smooth muscle cells (VSMC), including proliferation, migration, hypertrophy and inflammation. Angiotensin (1-7) appears to be the main effector peptide of ACE2 with vasodilatory, natriuretic and antiinflammatory properties. The cross-talk between the angiotensin II receptors may play an important role in maintaining cardiovascular homeostasis.

Keyword

Renin; Angiotensin II; Angiotensin-converting enzyme inhibitors; Angiotensin II receptor; Angiotensin-converting enzyme 2

MeSH Terms

Angiotensin II
Angiotensin-Converting Enzyme Inhibitors
Angiotensins
Blood Pressure
Cardiovascular Diseases
Heart Failure
Homeostasis
Hypertrophy
Inflammation
Monomeric GTP-Binding Proteins
Muscle, Smooth, Vascular
Myocardial Infarction
Receptors, Angiotensin
Renin
Renin-Angiotensin System*
Angiotensin II
Angiotensin-Converting Enzyme Inhibitors
Angiotensins
Monomeric GTP-Binding Proteins
Receptors, Angiotensin
Renin

Figure

• 

  Fig. 1 The Ras activation pathway by angiotensin II in the vascular smooth muscle cells. Angiotensin II stimulates the formation of Ras-GTP and the association of Ras-Raf. AT1 was proposed to activate Ras through Gq/phospholipase C-mediated intracellular Ca2+ elevation. A tyrosine kinase has been implicated in Ras activation by angiotensin II as well.2) Ang II: angiotensin II, AT1: angiotensin II type 1 receptor, EGFR: epidermal growth factor receptor, HB-EGF: heparin-binding EGF-like growth factor, ADAM: a disintegrin and metalloprotease, PLC: phospholiase-C, ROS: reactive oxygen species, GDP: guanosine diphosphate, GTP: guanosine triphosphate, MEK: mitogen-activated protein kinase (MAPK) kinase, ERK: extracellular signal-regulated kinase, Mnk: MAPK interacting kinase, PI3K: phosphoinositide 3 kinase, PKB: protein kinase B, mTOR: mammalian target of rapamycin, PHAS-1: phosphorylated heat-and acid-stable protein, eIF4E: eukaryotic initiation factor-4E.

• 

  Fig. 2 Action site of angiotensin-converting enzyme (ACE). ACE cleaves the C-terminal dipeptide from angiotensin I and bradykinin. Thus, ACE is strategically poised to regulate the balance between the reninangiotensin system and the kallikrein-kinin system.40)

• 

  Fig. 3 Overview of the renin-angiotensin pathway. After its formation from angiotensinogen by renin, angiotensin I can be further cleaved by angiotensin-converting enzyme (ACE) to yield angiotensin II, or it is alternatively converted by ACE2 to angiotensin (1-9). BK: bradykinin, NO: nitric oxide.19)

• 

  Fig. 4 Pathways of angiotensin II formation and the proposed role of angiotensin II receptors. ACE: angiotensin-converting enzyme, AT1R, AT2R, AT3R, AT4R: angiotensin II types 1, 2, 3 and 4 receptors, CAGE: chymostatin-sensitive angiotensin II-generating enzyme, PAI-1: plasminogen activator inhibitor-1.1)

Reference

1. Duprez DA. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens. 2006. 24:983–991.

2. Ohtsu H, Suzuki H, Nakashima H, et al. Angiotensin II signal transduction through small GTP-binding proteins: mechanism and significance in vascular smooth muscle cells. Hypertension. 2006. 48:534–540.

3. Kim KB. The role of angiotensin receptor antagonist in patients with hypertension and cardiovascular diseases. Korean Circ J. 1999. 29:335–340.

4. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens Suppl. 2005. 23:S9–S17.

5. Burnier M, Zanchi A. Blockade of the renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens. 2006. 24:11–25.

6. Weber MA. Hypertension treatment and implications of recent cardiovascular outcome trials. J Hypertens Suppl. 2006. 24:S37–S44.

7. Sokol SI, Portnay EL, Curtis JP, et al. Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke. Neurology. 2004. 63:208–213.

8. Sleight P, Yusuf S. New evidence on the importance of the renin-angiotensin system in the treatment of higher-risk patients with hypertension. J Hypertens. 2003. 21:1599–1608.

9. Jeon ES. Role of angiotensin II receptor blockers in the treatment of congestive heart failure. Korean Circ J. 2002. 32:1039–1045.

10. Mancia G. Total cardiovascular risk: a new treatment concept. J Hypertens Suppl. 2006. 24:S17–S24.

11. Danilczyk U, Penninger JM. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res. 2006. 98:463–471.

12. Farmer JA. Renin angiotensin system and ASCVD. Curr Opin Cardiol. 2000. 15:141–150.

13. Ulfendahl HR, Aurell M. Renin-Angiotensin: a centenary symposium of the discovery of the renin-angiotensin system. 1998. London: Portland Press;1–12.

14. Suh SY, Park CG, Chwe UR, et al. Plasma renin activity and clinical implication in Korean hypertensive patients. Korean Circ J. 2005. 35:658–664.

15. Duff JL, Marrero MB, Paxton WG, Schieffer B, Bernstein KE, Berk BC. Angiotensin II signal transduction and the mitogen-activated protein kinase pathway. Cardiovasc Res. 1995. 30:511–517.

16. Pan L, Gross KW. Transcriptional regulation of renin. Hypertension. 2005. 45:3–8.

17. Rosendorff C. The renin-angiotensin system and vascular hypertrophy. J Am Coll Cardiol. 1996. 28:803–812.

18. Beierwaltes WH. Izzo JL, Black HR, editors. Renin synthesis and secretion. Hypertension Primer. 2003. 3rd ed. Philadelphia: Lippincott Williams & Wilkins;14–17.

19. Krum H, Gilbert RE. Novel therapies blocking the renin-angiotensin-aldosterone system in the management of hypertension and related disorders. J Hypertens. 2007. 25:25–35.

20. Berk BC, Corson MA. Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circ Res. 1997. 80:607–616.

21. de Leeuw PW. How do angiotensin II receptor antagonists affect blood pressure? Am J Cardiol. 1999. 84:5K–6K.

22. Min LJ, Mogi M, Li JM, Iwanami J, Iwai M, Horiuchi M. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res. 2005. 97:434–442.

23. Zhang Y, Griendling KK, Dikalova A, Owens GK, Taylor WR. Vascular hypertrophy in angiotensin II-induced hypertension is mediated by vascular smooth muscle cell-derived H₂O₂. Hypertension. 2005. 46:732–737.

24. Ushio-Fukai M, Zuo L, Ikeda S, Tojo T, Patrushev NA, Alexander RW. cAbl tyrosine kinase mediates reactive oxygen species and caveolin-dependent AT₁ receptor signaling in vascular smooth muscle. Circ Res. 2005. 97:829–836.

25. Dikalova A, Clempus R, Lassegue B, et al. Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation. 2005. 112:2668–2676.

26. Shimokawa H. Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Phamacol. 2002. 39:319–327.

27. Calo LA, Pessina AC. RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone: evidence from studies in humans. J Hypertens. 2007. 25:259–264.

28. Smith NJ, Luttrell LM. Signal switching, crosstalk, and arrestin scaffolds: novel G protein-coupled receptor signaling in cardiovascular disease. Hypertension. 2006. 48:173–179.

29. Yang CH, Lee SH, Park TH, et al. Gene expression profile of volume-overloaded human ventricular myocardium prior to developing heart failure. Korean Circ J. 2005. 35:649–657.

30. Fleming I. Signaling by the angiotensin-converting enzyme. Circ Res. 2006. 98:887–896.

31. Willenheimer R, Dahloef B, Rydberg E, Erhardt L. AT₁-receptor blockers in hypertension and heart failure: clinical experience and future directions. Eur Heart J. 1999. 20:997–1008.

32. Hollenberg NK. Hypertension, small arteries, and pathways for angiotensin II generation. Circulation. 2000. 101:1641–1642.

33. Unger T, Culman J, Peter G. Angiotensin II receptor blockade and end-organ protection: pharmacological rationale and evidence. J Hypertens Suppl. 1998. 16:S3–S9.

34. Diez J. Profibrotic effects of angiotensin II in the heart. Hypertension. 2004. 43:1164–1165.

35. Wolf G, Wenzel UO. Angiotensin II and cell cycle regulation. Hypertension. 2004. 43:693–698.

36. Kim YH, Son JH, Piao H, et al. Role of angiotensin II type 1A receptor-mediated signaling in the development of pressure overload-induced left ventricular hypertrophy and fibrosis. Korean Circ J. 2006. 36:626–634.

37. Kim KM, Kim IS, Park SJ, et al. Effects of angiotensin II on the growth of vascular smooth muscle cells. Korean Circ J. 1999. 29:209–215.

38. Dielis AW, Smid M, Spronk HM, et al. The prothrombotic paradox of hypertension: role of the renin-angiotensin and kallikrein-kinin systems. Hypertension. 2005. 46:1236–1242.

39. Sampaio WO, Souza dos Santos RA, Faria-Silva R, de Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007. 49:185–192.

40. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998. 97:1411–1420.

41. Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006. 98:1123–1133.

42. Goldberg LR, Jessup M. Stage B heart failure: management of asymptomatic left ventricular systolic dysfunction. Circulation. 2006. 113:2851–2860.

43. Kahan T. The importance of left ventricular hypertrophy in human hypertension. J Hypertens Suppl. 1998. 16:S23–S29.

44. Alfakin K, Reid S, Hall A, Sivananthan MU. The assessment of left ventricular hypertrophy in hypertension. J Hypertens. 2006. 24:1223–1230.

45. Gosse P. Left ventricular hypertrophy as a predictor of cardiovascular risk. J Hypertens Suppl. 2005. 23:S27–S33.

46. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990. 86:1343–1346.

47. Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin-converting enzyme gene (DCPI) (dipeptidyl carboxypeptidase I). Nucleic Acids Res. 1992. 20:1433.

48. Rosendorff C. Vascular hypertrophy in hypertension: role of the renin-angiotensin system. Mt Sinai J Med. 1998. 65:108–117.

49. Schiffrin EL. Effects of antihypertensive drugs on vascular remodeling: do they predict outcome in response to antihypertensive therapy? Curr Opin Nephrol Hypertens. 2001. 10:617–624.

50. Schulman IH, Zhou MS, Raij L. Cross-talk between angiotensin II receptor types 1 and 2: potential role in vascular remodeling in humans. Hypertension. 2007. 49:270–271.

51. Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001. 103:904–912.