The intracellular renin-angiotensin system in the heart

  • Rajesh Kumar
  • Vivek P. Singh
  • Kenneth M. BakerEmail author


Recently, several novel aspects of the renin-angiotensin system (RAS) were described, which potentially may change the therapeutic strategy to treat cardiovascular disease, in addition to enhancing understanding of this system’s mechanism of action. Most notably, identification of a functional intracellular RAS may address several unanswered questions regarding a direct role of angiotensin (Ang) II in cardiac remodeling and incomplete efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers or superiority of a renin inhibitor in cardiovascular disorders. We describe the physiology of the intracellular RAS, potential pathologic roles of intracellular Ang II, and the relevance of the intracellular system in view of recent clinical trials involving various RAS inhibitors.


Renin Valsartan Candesartan Aliskiren Renin Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Recommended Reading

  1. 1.
    Kumar R, Baker KM, Pan J: Cardiac and vascular reninangiotensin systems. In Hypertension and Hormone Mechanisms. Edited by Carey RM, edn 2. Totowa, NJ: Humana Press; 2007:23–42.Google Scholar
  2. 2.
    Kumar R, Boim MA: Diversity of pathways for intracellular angiotensin II synthesis. Curr Opin Nephrol Hypertens 2009, 18:33–39.PubMedCrossRefGoogle Scholar
  3. 3.
    Crowley SD, Gurley SB, Oliverio MI, et al.: Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 2005, 115:1092–1099.PubMedGoogle Scholar
  4. 4.
    Crowley SD, Gurley SB, Herrera MJ, et al.: Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci U S A 2006, 103:17985–17990.PubMedCrossRefGoogle Scholar
  5. 5.
    Siragy HM: Evidence for benefits of angiotensin receptor blockade beyond blood pressure control. Curr Hypertens Rep 2008, 10:261–267.PubMedCrossRefGoogle Scholar
  6. 6.
    Kumar R, Singh VP, Baker KM: The intracellular reninangiotensin system: a new paradigm. Trends Endocrinol Metab 2007, 18:208–214.PubMedCrossRefGoogle Scholar
  7. 7.
    Singh VP, Baker KM, Kumar R: Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol 2008, 294:H1675–H1684.PubMedCrossRefGoogle Scholar
  8. 8.
    Singh VP, Bao L, Khode R, et al.: Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes 2008, 57:3297–3306.PubMedCrossRefGoogle Scholar
  9. 9.
    Singh VP, Le B, Bhat VB, et al.: High glucose induced regulation of intracellular angiotensin II synthesis and nuclear redistribution in cardiac myocytes. Am J Physiol Heart Circ Physiol 2007, 293:H939–H948.PubMedCrossRefGoogle Scholar
  10. 10.
    Baker KM, Chernin MI, Schreiber T, et al.: Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy. Regul Pept 2004, 120:5–13.PubMedCrossRefGoogle Scholar
  11. 11.
    Baker KM, Kumar R: Intracellular angiotensin II induces cell proliferation independent of AT1 receptor. Am J Physiol Cell Physiol 2006, 291:C995–1001.PubMedCrossRefGoogle Scholar
  12. 12.
    Fukuda N, Satoh C, Hu WY, et al.: Production of angiotensin II by homogeneous cultures of vascular smooth muscle cells from spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 1999, 19:1210–1217.PubMedGoogle Scholar
  13. 13.
    Dell’Italia LJ, Husain A: Dissecting the role of chymase in angiotensin II formation and heart and blood vessel diseases. Curr Opin Cardiol 2002, 17:374–379.PubMedCrossRefGoogle Scholar
  14. 14.
    Miyazaki M, Takai S: Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase. J Pharmacol Sci 2006, 100:391–397.PubMedCrossRefGoogle Scholar
  15. 15.
    McDonald JE, Padmanabhan N, Petrie MC, et al.: Vasoconstrictor effect of the angiotensin-converting enzyme-resistant, chymase-specific substrate [Pro(11)(D)-Ala(12)] angiotensin I in human dorsal hand veins: in vivo demonstration of non-ace production of angiotensin II in humans. Circulation 2001, 104:1805–1808.PubMedCrossRefGoogle Scholar
  16. 16.
    Ju H, Gros R, You X, et al.: Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. Proc Natl Acad Sci U S A 2001, 98:7469–7474.PubMedCrossRefGoogle Scholar
  17. 17.
    Li M, Liu K, Michalicek J, et al.: Involvement of chymasemediated angiotensin II generation in blood pressure regulation. J Clin Invest 2004, 114:112–120.PubMedGoogle Scholar
  18. 18.
    Booz GW, Conrad KM, Hess AL, et al.: Angiotensin-IIbinding sites on hepatocyte nuclei. Endocrinology 1992, 130:3641–3649.PubMedCrossRefGoogle Scholar
  19. 19.
    Eggena P, Zhu JH, Clegg K, Barrett JD: Nuclear angiotensin receptors induce transcription of renin and angiotensinogen mRNA. Hypertension 1993, 22:496–501.PubMedGoogle Scholar
  20. 20.
    Pendergrass KD, Averill DB, Ferrario CM, et al.: Differential expression of nuclear AT1 receptors and angiotensin II within the kidney of the male congenic mRen2.Lewis rat. Am J Physiol Renal Physiol 2006, 290:F1497–F1506.PubMedCrossRefGoogle Scholar
  21. 21.
    Cristovam PC, Arnoni CP, de Andrade MC, et al.: ACE-and chymase-dependent angiotensin II generation in normal and glucose-stimulated human mesangial cells. Exp Biol Med (Maywood) 2008, 233:1035–1043.CrossRefGoogle Scholar
  22. 22.
    Lavrentyev EN, Estes AM, Malik KU: Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. Circ Res 2007, 101:455–464.PubMedCrossRefGoogle Scholar
  23. 23.
    Vidotti DB, Casarini DE, Cristovam PC, et al.: High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells. Am J Physiol Renal Physiol 2004, 286:F1039–F1045.PubMedCrossRefGoogle Scholar
  24. 24.
    Singh R, Leehey DJ: Effect of ACE inhibitors on angiotensin II in rat mesangial cells cultured in high glucose. Biochem Biophys Res Commun 2007, 357:1040–1045.PubMedCrossRefGoogle Scholar
  25. 25.
    Kumar R, Singh VP, Baker KM: The intracellular renin-angiotensin system: implications in cardiovascular remodeling. Curr Opin Nephrol Hypertens 2008, 17:168–173.PubMedCrossRefGoogle Scholar
  26. 26.
    Sherrod M, Liu X, Zhang X, Sigmund CD: Nuclear localization of angiotensinogen in astrocytes. Am J Physiol Regul Integr Comp Physiol 2004, 288:R539–546.PubMedGoogle Scholar
  27. 27.
    Sanghi S, Kumar R, Smith M, et al.: Activation of protein kinase A by atrial natriuretic peptide in neonatal rat cardiac fibroblasts: role in regulation of the local renin-angiotensin system. Regul Pept 2005, 132:1–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Krop M, Danser AH: Circulating versus tissue renin-angiotensin system: on the origin of (pro)renin. Curr Hypertens Rep 2008, 10:112–118.PubMedCrossRefGoogle Scholar
  29. 29.
    Singh VP, Baker KM, Kumar R: Intracellular angiotensin II is a positive regulator of the cardiac renin-angiotensin system. Hypertension 2008, 52:E91–E92.Google Scholar
  30. 30.
    Peters J, Clausmeyer S: Intracellular sorting of renin: cell type specific differences and their consequences. J Mol Cell Cardiol 2002, 34:1561–1568.PubMedCrossRefGoogle Scholar
  31. 31.
    Wanka H, Kessler N, Ellmer J, et al.: Cytosolic renin is targeted to mitochondria and induces apoptosis in H9c2 rat cardiomyoblasts. J Cell Mol Med 2008 (Epub ahead of print).Google Scholar
  32. 32.
    Peters J, Wanka H, Peters B, Hoffmann S: A renin transcript lacking exon 1 encodes for a non-secretory intracellular renin that increases aldosterone production in transgenic rats. J Cell Mol Med 2008, 12:1229–1237.PubMedCrossRefGoogle Scholar
  33. 33.
    Franken AA, Derkx FH, Man in’t Veld AJ, et al.: High plasma prorenin in diabetes mellitus and its correlation with some complications. J Clin Endocrinol Metab 1990, 71:1008–1015.PubMedCrossRefGoogle Scholar
  34. 34.
    Nguyen G, Delarue F, Burckle C, et al.: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002, 109:1417–1427.PubMedGoogle Scholar
  35. 35.
    Peters J, Farrenkopf R, Clausmeyer S, et al.: Functional significance of prorenin internalization in the rat heart. Circ Res 2002, 90:1135–1141.PubMedCrossRefGoogle Scholar
  36. 36.
    De Mello WC: Is an intracellular renin-angiotensin system involved in control of cell communication in heart? J Cardiovasc Pharmacol 1994, 23:640–646.PubMedCrossRefGoogle Scholar
  37. 37.
    De Mello WC: Influence of intracellular renin on heart cell communication. Hypertension 1995, 25:1172–1177.PubMedGoogle Scholar
  38. 38.
    Haller H, Lindschau C, Erdmann B, et al.: Effects of intracellular angiotensin II in vascular smooth muscle cells. Circ Res 1996, 79:765–772.PubMedGoogle Scholar
  39. 39.
    Filipeanu CM, Brailoiu E, Kok JW, et al.: Intracellular angiotensin II elicits Ca2+ increases in A7r5 vascular smooth muscle cells. Eur J Pharmacol 2001, 420:9–18.PubMedCrossRefGoogle Scholar
  40. 40.
    Filipeanu CM, Henning RH, de Zeeuw D, Nelemans A: Intracellular angiotensin II and cell growth of vascular smooth muscle cells. Br J Pharmacol 2001, 132:1590–1596.PubMedCrossRefGoogle Scholar
  41. 41.
    Filipeanu CM, Brailoiu E, Henning RH, et al.: Intracellular angiotensin II inhibits heterologous receptor stimulated Ca2+ entry. Life Sci 2001, 70:171–180.PubMedCrossRefGoogle Scholar
  42. 42.
    Cook JL, Zhang Z, Re RN: In vitro evidence for an intracellular site of angiotensin action. Circ Res 2001, 89:1138–1146.PubMedCrossRefGoogle Scholar
  43. 43.
    Cook JL, Re R, Alam J, et al.: Intracellular angiotensin II fusion protein alters AT1 receptor fusion protein distribution and activates CREB. J Mol Cell Cardiol 2004, 36:75–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Brailoiu E, Filipeanu CM, Tica A, et al.: Contractile effects by intracellular angiotensin II via receptors with a distinct pharmacological profile in rat aorta. Br J Pharmacol 1999, 126:1133–1138.PubMedCrossRefGoogle Scholar
  45. 45.
    Sowers JR, Khoury S, Standley P, et al.: Mechanisms of hypertension in diabetes. Am J Hypertens 1991, 4:177–182.PubMedGoogle Scholar
  46. 46.
    Mazzolai L, Nussberger J, Aubert JF, et al.: Blood pressureindependent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 1998, 31:1324–1330.PubMedGoogle Scholar
  47. 47.
    Xiao HD, Fuchs S, Campbell DJ, et al.: Mice with cardiacrestricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol 2004, 165:1019–1032.PubMedGoogle Scholar
  48. 48.
    van Kats JP, Methot D, Paradis P, et al.: Use of a biological peptide pump to study chronic peptide hormone action in transgenic mice. Direct and indirect effects of angiotensin II on the heart. J Biol Chem 2001, 276:44012–44017.PubMedCrossRefGoogle Scholar
  49. 49.
    Paradis P, Dali-Youcef N, Paradis FW, et al.: Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A 2000, 97:931–936.PubMedCrossRefGoogle Scholar
  50. 50.
    Reudelhuber TL, Bernstein KE, Delafontaine P: Is angiotensin II a direct mediator of left ventricular hypertrophy? Time for another look. Hypertension 2007, 49:1196–1201.PubMedCrossRefGoogle Scholar
  51. 51.
    Dell’italia LJ, Balcells E, Meng QC, et al.: Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am J Physiol 1997, 273:H961–H970.PubMedGoogle Scholar
  52. 52.
    Sumida Y, Umemura S, Tamura K, et al.: Increased cardiac angiotensin II receptors in angiotensinogen-deficient mice. Hypertension 1998, 31:45–49.PubMedGoogle Scholar
  53. 53.
    Parving HH, Persson F, Lewis JB, et al.: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008, 358:2433–2446.PubMedCrossRefGoogle Scholar
  54. 54.
    Boccara F, Cohen A: Interplay of diabetes and coronary heart disease on cardiovascular mortality. Heart 2004, 90:1371–1373.PubMedCrossRefGoogle Scholar
  55. 55.
    Okin PM, Devereux RB, Gerdts E, et al.: Impact of diabetes mellitus on regression of electrocardiographic left ventricular hypertrophy and the prediction of outcome during antihypertensive therapy: the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study. Circulation 2006, 113:1588–1596.PubMedCrossRefGoogle Scholar
  56. 56.
    Turnbull F, Neal B, Algert C, et al.: Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005, 165:1410–1419.PubMedCrossRefGoogle Scholar
  57. 57.
    Weber MA, Giles TD: Inhibiting the renin-angiotensin system to prevent cardiovascular diseases: do we need a more comprehensive strategy? Rev Cardiovasc Med 2006, 7:45–54.PubMedGoogle Scholar
  58. 58.
    Yusuf S, Teo KK, Pogue J, et al.: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008, 358:1547–1559.PubMedCrossRefGoogle Scholar
  59. 59.
    Mogensen CE, Neldam S, Tikkanen I, et al.: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000, 321:1440–1444.PubMedCrossRefGoogle Scholar
  60. 60.
    Bakris GL, Ruilope L, Locatelli F, et al.: Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int 2007, 72:879–885.PubMedCrossRefGoogle Scholar
  61. 61.
    Pfeffer MA, McMurray JJ, Velazquez EJ, et al.: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003, 349:1893–1906.PubMedCrossRefGoogle Scholar
  62. 62.
    Pfeffer MA, Swedberg K, Granger CB, et al.: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003, 362:759–766.PubMedCrossRefGoogle Scholar
  63. 63.
    Oparil S, Yarows SA, Patel S, et al.: Dual inhibition of the renin system by aliskiren and valsartan. Lancet 2007, 370:1126–1127.PubMedCrossRefGoogle Scholar
  64. 64.
    Uresin Y, Taylor AA, Kilo C, et al.: Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst 2007, 8:190–198.PubMedCrossRefGoogle Scholar
  65. 65.
    Epstein M: Re-examining RAS-blocking treatment regimens for abrogating progression of chronic kidney disease. Nat Clin Pract Nephrol 2009, 5:12–13.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Rajesh Kumar
  • Vivek P. Singh
  • Kenneth M. Baker
    • 1
    Email author
  1. 1.TempleUSA

Personalised recommendations