Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Key developments in renin–angiotensin–aldosterone system inhibition

Nature Reviews Nephrology volume 9, pages 26–36 (2013)Cite this article

Subjects

Abstract

The renin–angiotensin–aldosterone system (RAAS) was initially thought to be fairly simple. However, this idea has been challenged following the development of RAAS blockers, including renin inhibitors, angiotensin-converting-enzyme (ACE) inhibitors, type 1 angiotensin II (AT1)-receptor blockers and mineralocorticoid-receptor antagonists. Consequently, new RAAS components and pathways that might contribute to the effectiveness of these drugs and/or their adverse effects have been identified. For example, an increase in renin levels during RAAS blockade might result in harmful effects via stimulation of the prorenin receptor (PRR), and prorenin—the inactive precursor of renin—might gain enzymatic activity on PRR binding. The increase in angiotensin II levels that occurs during AT1-receptor blockade might result in beneficial effects via stimulation of type 2 angiotensin II receptors. Moreover, angiotensin 1–7 levels increase during ACE inhibition and AT1-receptor blockade, resulting in Mas receptor activation and the induction of cardioprotective and renoprotective effects, including stimulation of tissue repair by stem cells. Finally, a role of angiotensin II in sodium and potassium handling in the distal nephron has been identified. This finding is likely to have important implications for understanding the effects of RAAS inhibition on whole body sodium and potassium balance.

Key Points

  • Interactions between renin, prorenin and the prorenin receptor (PRR) have not been confirmed in vivo and seem unlikely because of the low levels of renin and prorenin in blood

  • Given the role of the PRR in V-type proton ATPase integrity and Wnt signalling, renin–angiotensin–aldosterone system (RAAS)-independent functions of the PRR seems more likely than RAAS-dependent functions

  • Under certain pathological conditions, type 2 angiotensin II (AT2) receptors mimic type 1 angiotensin II (AT1) receptor function and exert detrimental effects including vasoconstriction and hypertrophy

  • Stimulating angiotensin 1–7 generation or using stable angiotensin 1–7 analogues to activate the Mas receptor is a promising new strategy to improve tissue repair by stem cells

  • Angiotensin II affects the activity of the main sodium and potassium transporters in the distal nephron: the sodium chloride cotransporter, epithelial sodium channel and renal outer medullary potassium channel

  • Synergistic actions of angiotensin II and aldosterone on sodium and potassium transport in the distal nephron help to explain the effects of RAAS inhibition on renal sodium and potassium excretion

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: New developments in the renin–angiotensin-system cascade.
Figure 2: The aldosterone paradox.

Similar content being viewed by others

References

  1. Klotz, S., Burkhoff, D., Garrelds, I. M., Boomsma, F. & Danser, A. H. J. The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renin-angiotensin-aldosterone system: therapeutic consequences? Eur. Heart J. 30, 805–812 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. van Kats, J. P. et al. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II. Circulation 102, 1556–1563 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Ma, T. K., Kam, K. K., Yan, B. P. & Lam, Y. Y. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br. J. Pharmacol. 160, 1273–1292 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Verdonk, K., Danser, A. H. J. & van Esch, J. H. M. Angiotensin II type 2 receptor agonists: where should they be applied? Expert Opin. Investig. Drugs 21, 501–513 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. van Esch, J. H. M. et al. AT2 receptor-mediated vasodilation in the mouse heart depends on AT1A receptor activation. Br. J. Pharmacol. 148, 452–458 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Santos, R. A. et al. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc. Natl Acad. Sci. USA 100, 8258–8263 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Danser, A. H. Novel drugs targeting hypertension: renin inhibitors. J. Cardiovasc. Pharmacol. 50, 105–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Danser, A. H. J. The increase in renin during renin inhibition: does it result in harmful effects by the (pro)renin receptor? Hypertens. Res. 33, 4–10 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Batenburg, W. W., Jansen, P. M., van den Bogaerdt, A. J. & Danser, A. H. J. Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase. Cardiovasc. Res. 94, 136–143 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Chai, W. et al. Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiac mineralocorticoid receptors? J. Hypertens. 28, 1044–1053 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Chai, W. et al. Nongenomic effects of aldosterone in the human heart. Interaction with angiotensin II. Hypertension 46, 701–706 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Batenburg, W. W. et al. Prorenin is the endogenous agonist of the (pro)renin receptor. Binding kinetics of renin and prorenin in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor. J. Hypertens. 25, 2441–2453 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Lu, X., Danser, A. H. J. & Meima, M. E. HRP and prorenin: focus on the (pro)renin receptor and vacuolar H+-ATPase. Front. Biosci. (Schol. Ed.) 3, 1205–1215 (2011).

    Article  Google Scholar 

  15. Krop, M. & Danser, A. H. J. Circulating versus tissue renin-angiotensin system: on the origin of (pro)renin. Curr. Hypertens. Rep. 10, 112–118 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Saris, J. J. et al. Cardiomyocytes bind and activate native human prorenin: role of soluble mannose 6-phosphate receptors. Hypertension 37, 710–715 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Feldt, S. et al. Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 51, 682–688 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Suzuki, F. et al. Human prorenin has “gate and handle” regions for its non-proteolytic activation. J. Biol. Chem. 278, 22217–22222 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Ichihara, A. et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J. Clin. Invest. 114, 1128–1135 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ichihara, A. et al. Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J. Am. Soc. Nephrol. 17, 1950–1961 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Kaneshiro, Y. et al. Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. J. Am. Soc. Nephrol. 18, 1789–1795 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Kaneshiro, Y. et al. Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats. Kidney Int. 70, 641–646 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Jansen, P. M., Hofland, J., van den Meiracker, A. H., de Jong, F. H. & Danser, A. H. J. Renin and prorenin have no direct effect on aldosterone synthesis in the human adrenocortical cell lines H295R and HAC15. J. Renin Angiotensin Aldosterone Syst. 13, 360–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Huang, Y. et al. Renin increases mesangial cell transforming growth factor-β1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 69, 105–113 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Clavreul, N., Sansilvestri-Morel, P., Magard, D., Verbeuren, T. J. & Rupin, A. (Pro)renin promotes fibrosis gene expression in HEK cells through a Nox4-dependent mechanism. Am. J. Physiol. Renal Physiol. 300, F1310–F1318 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Sakoda, M. et al. Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes. Am. J. Hypertens. 23, 575–580 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, J., Gu, C., Noble, N. A., Border, W. A. & Huang, Y. Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis. Am. J. Physiol. Renal Physiol. 301, F723–F732 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Melnyk, R. A., Tam, J., Boie, Y., Kennedy, B. P. & Percival, M. D. Renin and prorenin activate pathways implicated in organ damage in human mesangial cells independent of angiotensin II production. Am. J. Nephrol. 30, 232–243 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Cheng, H., Fan, X., Moeckel, G. W. & Harris, R. C. Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)renin receptor expression. J. Am. Soc. Nephrol. 22, 1240–1251 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang, J. & Siragy, H. M. Glucose promotes the production of interleukine-1β and cyclooxygenase-2 in mesangial cells via enhanced (pro)renin receptor expression. Endocrinology 150, 5557–5565 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Siragy, H. M. & Huang, J. Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp. Physiol. 93, 709–714 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Matavelli, L., Huang, J. & Siragy, H. M. (Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. Clin. Exp. Pharmacol. Physiol. 37, 277–282 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Feldman, D. L. et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mREN-2)-27 rats. Hypertension 52, 130–136 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Krebs, C. et al. Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats. Kidney Int. 72, 725–730 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Hirose, T. et al. Increased expression of (pro)renin receptor in the remnant kidneys of 5/6 nephrectomized rats. Regul. Pept. 159, 93–99 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Takahashi, K. et al. Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy. Peptides 31, 1405–1408 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Danser, A. H. J. et al. Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J. Hypertens. 16, 853–862 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Burcklé, C. A. et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension 47, 552–556 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Batenburg, W. W. et al. Renin- and prorenin-induced effects in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor: does (pro)renin-(pro)renin receptor interaction actually occur? Hypertension 58, 1111–1119 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Peters, B. et al. Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis. J. Hypertens. 26, 102–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Campbell, D. J., Karam, H., Ménard, J., Bruneval, P. & Mullins, J. J. Prorenin contributes to angiotensin peptide formation in transgenic rats with rat prorenin expression targeted to the liver. Hypertension 54, 1248–1253 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Mercure, C., Prescott, G., Lacombe, M. J., Silversides, D. W. & Reudelhuber, T. L. Chronic increases in circulating prorenin are not associated with renal or cardiac pathologies. Hypertension 53, 1062–1069 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Campbell, D. J. et al. Activity assays and immunoassays for plasma renin and prorenin: information provided and precautions necessary for accurate measurement. Clin. Chem. 55, 867–877 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Richer-Giudicelli, C. et al. Haemodynamic effects of dual blockade of the renin-angiotensin system in spontaneously hypertensive rats: influence of salt. J. Hypertens. 22, 619–627 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. de Boer, R. A. et al. Dual RAAS suppression: recent developments and implications in light of the ALTITUDE study. J. Renin Angiotensin Aldosterone Syst. 13, 409–412 (2012).

    Article  PubMed  Google Scholar 

  46. Advani, A. et al. The (pro)renin receptor: site-specific and functional linkage to the vacuolar H+-ATPase in the kidney. Hypertension 54, 261–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Riediger, F. et al. Prorenin receptor is essential for podocyte autophagy and survival. J. Am. Soc. Nephrol. 22, 2193–2202 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cruciat, C. M. et al. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327, 459–463 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. van Esch, J. H. M. et al. Handle region peptide counteracts the beneficial effects of the renin inhibitor aliskiren in spontaneously hypertensive rats. Hypertension 57, 852–858 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Vázquez, E. et al. Angiotensin II-dependent induction of AT2 receptor expression after renal ablation. Am. J. Physiol. Renal Physiol. 288, F207–F213 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. He, M. et al. Angiotensin II type 2 receptor mediated angiotensin II and high glucose induced decrease in renal prorenin/renin receptor expression. Mol. Cell Endocrinol. 315, 188–194 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Ruiz-Ortega, M. et al. Renal expression of angiotensin type 2 (AT2) receptors during kidney damage. Kidney Int. Suppl. S21–S26 (2003).

  53. Ichiki, T. et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 377, 748–750 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Hein, L., Barsh, G. S., Pratt, R. E., Dzau, V. J. & Kobilka, B. K. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature 377, 744–747 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Gross, V. et al. Inhibition of pressure natriuresis in mice lacking the AT2 receptor. Kidney Int. 57, 191–202 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Benndorf, R. A. et al. Angiotensin II type 2 receptor deficiency aggravates renal injury and reduces survival in chronic kidney disease in mice. Kidney Int. 75, 1039–1049 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Ma, J. et al. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int. 53, 937–944 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Tanaka, M. et al. Vascular response to angiotensin II is exaggerated through an upregulation of AT1 receptor in AT2 knockout mice. Biochem. Biophys. Res. Commun. 258, 194–198 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Padia, S. H., Howell, N. L., Siragy, H. M. & Carey, R. M. Renal angiotensin type 2 receptors mediate natriuresis via angiotensin III in the angiotensin II type 1 receptor-blocked rat. Hypertension 47, 537–544 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. van Esch, J. H. M., Oosterveer, C. R., Batenburg, W. W., van Veghel, R. & Danser, A. H. J. Effects of angiotensin II and its metabolites in the rat coronary vascular bed: is angiotensin III the preferred ligand of the angiotensin AT2 receptor? Eur. J. Pharmacol. 588, 286–293 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Padia, S. H. et al. Conversion of renal angiotensin II to angiotensin III is critical for AT2 receptor-mediated natriuresis in rats. Hypertension 51, 460–465 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Padia, S. H. et al. Intrarenal aminopeptidase N inhibition augments natriuretic responses to angiotensin III in angiotensin type 1 receptor-blocked rats. Hypertension 49, 625–630 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Ali, Q. & Hussain, T. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats. Hypertens. Res. 35, 654–660 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Matavelli, L. C., Huang, J. & Siragy, H. M. Angiotensin AT2 receptor stimulation inhibits early renal inflammation in renovascular hypertension. Hypertension 57, 308–313 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Hilliard, L. M. et al. Sex-specific influence of angiotensin type 2 receptor stimulation on renal function: a novel therapeutic target for hypertension. Hypertension 59, 409–414 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Verdonk, K. et al. Compound 21 induces vasorelaxation via an endothelium and angiotensin II type 2 receptor-independent mechanism. Hypertension 60, 722–729 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Cao, Z. et al. Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury. J. Am. Soc. Nephrol. 13, 1773–1787 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Esteban, V. et al. Angiotensin II, via AT1 and AT2 receptors and NF-κB pathway, regulates the inflammatory response in unilateral ureteral obstruction. J. Am. Soc. Nephrol. 15, 1514–1529 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Wolf, G. et al. Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J. Clin. Invest. 100, 1047–1058 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Siragy, H. M. & Carey, R. M. Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model. Hypertension 33, 1237–1242 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Rehman, A. et al. Angiotensin type 2 receptor agonist compound 21 reduces vascular injury and myocardial fibrosis in stroke-prone spontaneously hypertensive rats. Hypertension 59, 291–299 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Moltzer, E., Verkuil, A. V., van Veghel, R., Danser, A. H. J. & van Esch, J. H. M. Effects of angiotensin metabolites in the coronary vascular bed of the spontaneously hypertensive rat: loss of angiotensin II type 2 receptor-mediated vasodilation. Hypertension 55, 516–522 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. You, D. et al. High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation 111, 1006–1011 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Blood Pressure Lowering Treatment Trialists' Collaboration et al. Blood pressure-dependent and independent effects of agents that inhibit the renin–angiotensin system. J. Hypertens. 25, 951–958 (2007).

  75. Vickers, C. et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J. Biol. Chem. 277, 14838–14843 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Iusuf, D., Henning, R. H., van Gilst, W. H. & Roks, A. J. Angiotensin-(1–7): pharmacological properties and pharmacotherapeutic perspectives. Eur. J. Pharmacol. 585, 303–312 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Ferreira, A. J. et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension 55, 207–213 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Moon, J. Y. et al. Attenuating effect of angiotensin-(1–7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-Ay/Ta mice. Am. J. Physiol. Renal Physiol. 300, F1271–F1282 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Benter, I. F. et al. Angiotensin-(1–7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester. J. Cardiovasc. Pharmacol. 57, 559–567 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Benter, I. F., Yousif, M. H., Anim, J. T., Cojocel, C. & Diz, D. I. Angiotensin-(1–7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am. J. Physiol. Heart Circ. Physiol. 290, H684–H691 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Raffai, G., Durand, M. J. & Lombard, J. H. Acute and chronic angiotensin-(1–7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats. Am. J. Physiol. Heart Circ. Physiol. 301, H1341–H1352 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rabelo, L. A. et al. Ablation of angiotensin (1–7) receptor Mas in C57Bl/6 mice causes endothelial dysfunction. J. Am. Soc. Hypertens. 2, 418–424 (2008).

    Article  PubMed  Google Scholar 

  83. Sampaio, W. O., Henrique de Castro, C., Santos, R. A., Schiffrin, E. L. & Touyz, R. M. Angiotensin-(1–7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension 50, 1093–1098 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Wolf, G., Ziyadeh, F. N., Zahner, G. & Stahl, R. A. Angiotensin II-stimulated expression of transforming growth factor β in renal proximal tubular cells: attenuation after stable transfection with the c-mas oncogene. Kidney Int. 48, 1818–1827 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Zimpelmann, J. & Burns, K. D. Angiotensin-(1–7) activates growth-stimulatory pathways in human mesangial cells. Am. J. Physiol. Renal Physiol. 296, F337–F346 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Kostenis, E. et al. G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation 111, 1806–1813 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Strauer, B. E. & Steinhoff, G. 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. J. Am. Coll. Cardiol. 58, 1095–1104 (2011).

    Article  PubMed  Google Scholar 

  88. El-Ansary, M., Saadi, G. & Abd El-Hamid, S. Mesenchymal stem cells are a rescue approach for recovery of deteriorating kidney function. Nephrology (Carlton) 17, 650–657 (2012).

    Article  Google Scholar 

  89. Perico, N. et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin. J. Am. Soc. Nephrol. 6, 412–422 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Strawn, W. B., Richmond, R. S., Ann Tallant, E., Gallagher, P. E. & Ferrario, C. M. Renin-angiotensin system expression in rat bone marrow haematopoietic and stromal cells. Br. J. Haematol. 126, 120–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Rodgers, K. E. et al. Accelerated hematopoietic recovery with angiotensin-(1–7) after total body radiation. Int. J. Radiat. Biol. 88, 466–476 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Rodgers, K. E., Xiong, S. & diZerega, G. S. Accelerated recovery from irradiation injury by angiotensin peptides. Cancer Chemother. Pharmacol. 49, 403–411 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Wang, Y. et al. Circulating rather than cardiac angiotensin-(1–7) stimulates cardioprotection after myocardial infarction. Circ. Heart Fail. 3, 286–293 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Petty, W. J. et al. Phase I and pharmacokinetic study of angiotensin-(1–7), an endogenous antiangiogenic hormone. Clin. Cancer Res. 15, 7398–7404 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Marques, F. D. et al. An oral formulation of angiotensin-(1–7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. Hypertension 57, 477–483 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. de Vries, L. et al. Oral and pulmonary delivery of thioether-bridged angiotensin-(1–7). Peptides 31, 893–898 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Kluskens, L. D. et al. Angiotensin-(1–7) with thioether bridge: an angiotensin-converting enzyme-resistant, potent angiotensin-(1–7) analog. J. Pharmacol. Exp. Ther. 328, 849–854 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Durik, M. et al. The effect of the thioether-bridged, stabilized angiotensin-(1–7) analogue cyclic ang-(1–7) on cardiac remodeling and endothelial function in rats with myocardial infarction. Int. J. Hypertens. 2012, 536426 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Faria-Silva, R., Duarte, F. V. & Santos, R. A. Short-term angiotensin-(1–7) receptor MAS stimulation improves endothelial function in normotensive rats. Hypertension 46, 948–952 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Murca, T. M., Almeida, T. C., Raizada, M. K. & Ferreira, A. J. Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction. Exp. Physiol. 97, 699–709 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hernandez Prada, J. A. et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension 51, 1312–1317 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Meneton, P., Loffing, J. & Warnock, D. G. Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule. Am. J. Physiol. Renal Physiol. 287, F593–F601 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Saccomani, G., Mitchell, K. D. & Navar, L. G. Angiotensin II stimulation of Na+-H+ exchange in proximal tubule cells. Am. J. Physiol. 258, F1188–F1195 (1990).

    CAS  PubMed  Google Scholar 

  104. Kim, G. H. et al. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc. Natl Acad. Sci. USA 95, 14552–14557 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Masilamani, S., Kim, G. H., Mitchell, C., Wade, J. B. & Knepper, M. A. Aldosterone-mediated regulation of ENaC α, β, and γ subunit proteins in rat kidney. J. Clin. Invest. 104, R19–R23 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Beesley, A. H., Hornby, D. & White, S. J. Regulation of distal nephron K+ channels (ROMK) mRNA expression by aldosterone in rat kidney. J. Physiol. 509 (Pt 3), 629–634 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wald, H., Garty, H., Palmer, L. G. & Popovtzer, M. M. Differential regulation of ROMK expression in kidney cortex and medulla by aldosterone and potassium. Am. J. Physiol. 275, F239–F245 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. McCormick, J. A., Yang, C. L. & Ellison, D. H. WNK kinases and renal sodium transport in health and disease: an integrated view. Hypertension 51, 588–596 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Sandberg, M. B., Riquier, A. D., Pihakaski-Maunsbach, K., McDonough, A. A. & Maunsbach, A. B. Ang II provokes acute trafficking of distal tubule Na+-Cl- cotransporter to apical membrane. Am. J. Physiol. Renal Physiol. 293, F662–F669 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. van der Lubbe, N. et al. Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone. Kidney Int. 79, 66–76 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. van der Lubbe, N. et al. Aldosterone does not require angiotensin II to activate NCC through a WNK4–SPAK-dependent pathway. Pflügers Arch. 463, 853–863 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mamenko, M., Zaika, O., Ilatovskaya, D. V., Staruschenko, A. & Pochynyuk, O. Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone. J. Biol. Chem. 287, 660–671 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Sun, P., Yue, P. & Wang, W. H. Angiotensin II stimulates epithelial sodium channels in the cortical collecting duct of the rat kidney. Am. J. Physiol. Renal Physiol. 302, F679–F687 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Wei, Y., Zavilowitz, B., Satlin, L. M. & Wang, W. H. Angiotensin II inhibits the ROMK-like small conductance K channel in renal cortical collecting duct during dietary potassium restriction. J. Biol. Chem. 282, 6455–6462 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. San-Cristobal, P. et al. Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc. Natl Acad. Sci. USA 106, 4384–4389 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Mujais, S. K., Kauffman, S. & Katz, A. I. Angiotensin II binding sites in individual segments of the rat nephron. J. Clin. Invest. 77, 315–318 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wang, T. & Giebisch, G. Effects of angiotensin II on electrolyte transport in the early and late distal tubule in rat kidney. Am. J. Physiol. 271, F143–F149 (1996).

    CAS  PubMed  Google Scholar 

  118. Frindt, G. & Palmer, L. G. Effects of dietary K on cell-surface expression of renal ion channels and transporters. Am. J. Physiol. Renal Physiol. 299, F890–F897 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wilson, F. H. et al. Human hypertension caused by mutations in WNK kinases. Science 293, 1107–1112 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Welling, P. A., Chang, Y. P., Delpire, E. & Wade, J. B. Multigene kinase network, kidney transport, and salt in essential hypertension. Kidney Int. 77, 1063–1069 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Castaneda-Bueno, M., Arroyo, J. P. & Gamba, G. Independent regulation of Na+ and K+ balance by the kidney. Med. Princ. Pract. 21, 101–114 (2012).

    Article  PubMed  Google Scholar 

  122. Chiga, M. et al. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 74, 1403–1409 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Vallon, V., Schroth, J., Lang, F., Kuhl, D. & Uchida, S. Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1. Am. J. Physiol. Renal Physiol. 297, F704–F712 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yue, P. et al. Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels. Kidney Int. 79, 423–431 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Glover, M. & O'Shaughnessy, K. M. SPAK and WNK kinases: a new target for blood pressure treatment? Curr. Opin. Nephrol. Hypertens. 20, 16–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Arroyo, J. P., Ronzaud, C., Lagnaz, D., Staub, O. & Gamba, G. Aldosterone paradox: differential regulation of ion transport in distal nephron. Physiology (Bethesda) 26, 115–123 (2011).

    CAS  Google Scholar 

  127. Hoorn, E. J., Nelson, J. H., McCormick, J. A. & Ellison, D. H. The WNK kinase network regulating sodium, potassium, and blood pressure. J. Am. Soc. Nephrol. 22, 605–614 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. O'Reilly, M. et al. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. J. Am. Soc. Nephrol. 17, 2402–2413 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Brater, D. C. Diuretic therapy. N. Engl. J. Med. 339, 387–395 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Vogt, L., Navis, G. & de Zeeuw, D. Renoprotection: a matter of blood pressure reduction or agent-characteristics? J. Am. Soc. Nephrol. 13 (Suppl. 3), S202–S207 (2002).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The angiotensin 1–7 research described in this review was supported by the Netherlands Heart Foundation (grant number 2010B009). E. J. Hoorn is supported by a grant from The Netherlands Organisation for Scientific Research (NWO, Veni grant 91612140).

Author information

Authors and Affiliations

  1. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, Rotterdam, 3015 GE, The Netherlands

    Bruno Sevá Pessôa, Koen Verdonk, Anton J. M. Roks & A. H. Jan Danser

  2. Division of Nephrology, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 50, Rotterdam, 3015 GE, The Netherlands

    Nils van der Lubbe & Ewout J. Hoorn

Authors
  1. Bruno Sevá Pessôa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nils van der Lubbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koen Verdonk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anton J. M. Roks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ewout J. Hoorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. H. Jan Danser
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, contributed substantially to discussion of the content and wrote the article. A. J. M. Roks, E. J. Hoorn and A. H. J. Danser reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to A. H. Jan Danser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sevá Pessôa, B., van der Lubbe, N., Verdonk, K. et al. Key developments in renin–angiotensin–aldosterone system inhibition. Nat Rev Nephrol 9, 26–36 (2013). https://doi.org/10.1038/nrneph.2012.249

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.249

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing