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:

Direct renin inhibition and the kidney

Nature Reviews Nephrology volume 6, pages 49–55 (2010)Cite this article

Abstract

Direct renin inhibition is a new means for blocking the renin–angiotensin system at the rate-limiting step of the cascade of events triggered by renin release—the interaction of renin with its physiological substrate angiotensinogen. The remarkable success of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers in the management of cardiovascular and renal disease has led to great interest in the potential of direct renin inhibitors. This Review focuses on the evidence that suggests that direct renin inhibitors might block the renin–angiotensin system in the kidney more completely than either angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The therapeutic implications of this evidence are also reviewed, as well as the possible mechanistic routes by which direct renin inhibition might exert its influence on the kidney.

Key Points

  • Direct renin inhibitors (DRIs) competitively bind to renin to prevent interaction between renin and angiotensinogen

  • Renin-catalyzed conversion of angiotensinogen to angiotensin I is the rate-limiting step in the event cascade that activates the renin–angiotensin system (RAS)

  • The DRI aliskiren is safe and as effective in reducing blood pressure as agents such as angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers

  • Preliminary evidence indicates that DRIs improve renovascular function to a greater extent than other RAS blockade agents

  • Although prorenin is an ostensibly inactive precursor of renin, growing evidence suggests that this protein might be involved in precipitating pathological processes in patients with diabetic nephropathy

  • The potential renoprotective effects of DRIs might be explained by their targeting of renin, the effect they might have on prorenin and by the lack of treatment-associated increase in plasma renin activity

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: The cascade that leads to the activation of the renin–angiotensin system.
Figure 2: Increase in renal plasma flow in healthy young men in response to pharmacological blockade of the renin–angiotensin system by different drugs and drug classes.
Figure 3: Dose-related increase in renal plasma flow in healthy patients on a low-sodium regimen in response to the administration of the direct renin inhibitor aliskiren.21
Figure 4: Mean geometric percentage change from baseline (2 weeks before randomization) in the urinary albumin-to-creatinine ratio a | overnight urinary albumin excretion rate b | and blood pressure measured while the patient was seated c | associated with the administration of 150 mg daily for 3 months, followed by the administration of 300 mg daily for another 3 months of aliskiren or placebo.22

Similar content being viewed by others

References

  1. Navar, L., Harrison-Bernard, L. M., Imig, J. D. & Mitchell, K. D. in Angiotensin II Receptor Antagonists 190 (eds Epstein, M. & Brunner, H. R.) 89–214 (Hanley & Belfus, Philadelphia, 2001).

    Google Scholar 

  2. Musini, V. M., Fortin, P. M., Bassett, K. & Wright, J. M. Blood pressure lowering efficacy of renin inhibitors for primary hypertension: a Cochrane systematic review. J. Hum. Hypertens. 23, 495–502 (2009).

    Article  CAS  Google Scholar 

  3. Stanton, A., Jensen, C., Nussberger, J. & O'Brien, E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 42, 1137–1143 (2003).

    Article  CAS  Google Scholar 

  4. Pool, J. L. et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am. J. Hypertens. 20, 11–20 (2007).

    Article  CAS  Google Scholar 

  5. Villamil, A. et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J. Hypertens. 25, 217–226 (2007).

    Article  CAS  Google Scholar 

  6. Oparil, S. et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial. Lancet 370, 221–229 (2007).

    Article  CAS  Google Scholar 

  7. Hollenberg, N. K. Renin inhibition: what are the clinical perspectives? Semin. Nephrol. 27, 511–518 (2007).

    Article  CAS  Google Scholar 

  8. Krop, M. et al. Aliskiren accumulates in renin secretory granules and binds plasma prorenin. Hypertension 52, 1076–1083 (2008).

    Article  CAS  Google Scholar 

  9. Muller, D. N. & Luft, F. C. Renin receptor blockade: a better strategy for renal protection than renin-angiotensin system inhibition? Curr. Hypertens. Rep. 10, 405–409 (2008).

    Article  CAS  Google Scholar 

  10. Schefe, J. H. et al. Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren. J. Hypertens. 26, 1787–1794 (2008).

    Article  CAS  Google Scholar 

  11. Skeggs, L. T. Jr, Kahn, J. R., Lentz, K. & Shumway, N. P. The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J. Exp. Med. 106, 439–453 (1957).

    Article  CAS  Google Scholar 

  12. Hollenberg, N. K. Implications of species difference for clinical investigation: studies on the renin-angiotensin system. Hypertension 35, 150–154 (2000).

    Article  CAS  Google Scholar 

  13. Allan, D. R., Hui, K. Y., Coletti, C. & Hollenberg, N. K. Renin vs. angiotensin-converting enzyme inhibition in the rat: consequences for plasma and renal tissue angiotensin. J. Pharmacol. Exp. Ther. 283, 661–665 (1997).

    CAS  PubMed  Google Scholar 

  14. Neisius, D., Wood, J. M. & Hofbauer, K. G. Renal vasodilatation after inhibition of renin or converting enzyme in marmoset. Am. J. Physiol. 251, H897–H902 (1986).

    CAS  PubMed  Google Scholar 

  15. El Amrani, A. I., Menard, J., Gonzales, M. F. & Michel, J. P. Effects of blocking the angiotensin II receptor, converting enzyme, and renin activity on the renal hemodynamics of normotensive guinea pigs. J. Cardiovasc. Pharmacol. 22, 231–239 (1993).

    Article  CAS  Google Scholar 

  16. Verburg, K. M., Kleinert, H. D., Chekal, M. A., Kadam, J. R. & Young, G. A. Renal hemodynamic and excretory responses to renin inhibition induced by A-64662. J. Pharmacol. Exp. Ther. 252, 449–455 (1990).

    CAS  PubMed  Google Scholar 

  17. Huang, Y. et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 69, 105–113 (2006).

    Article  CAS  Google Scholar 

  18. Feldt, S., Maschke, U., Dechend, R., Luft, F. C. & Muller, D. N. The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling. J. Am. Soc. Nephrol. 19, 743–748 (2008).

    Article  CAS  Google Scholar 

  19. Cordero, P. et al. Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans. Hypertension 17, 510–516 (1991).

    Article  CAS  Google Scholar 

  20. Hollenberg, N. K. & Fisher, N. D. Renal circulation and blockade of the renin-angiotensin system. Is Angiotensin-converting enzyme inhibition the last word? Hypertension 26, 602–609 (1995).

    Article  CAS  Google Scholar 

  21. Fisher, N. D., Jan Danser, A. H., Nussberger, J., Dole, W. P. & Hollenberg, N. K. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation 117, 3199–3205 (2008).

    Article  CAS  Google Scholar 

  22. Parving, H. H., Persson, F., Lewis, J. B., Lewis, E. J. & Hollenberg, N. K. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N. Engl. J. Med. 358, 2433–2446 (2008).

    Article  CAS  Google Scholar 

  23. Parving, H. H. et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol. Dial. Transplant. 24, 1663–1671 (2009).

    Article  CAS  Google Scholar 

  24. Luetscher, J. A., Kraemer, F. B., Wilson, D. M., Schwartz, H. C. & Bryer-Ash, M. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N. Engl. J. Med. 312, 1412–1417 (1985).

    Article  CAS  Google Scholar 

  25. Luetscher, J. A. & Kraemer, F. B. Microalbuminuria and increased plasma prorenin. Prevalence in diabetics followed up for four years. Arch. Intern. Med. 148, 937–941 (1988).

    Article  CAS  Google Scholar 

  26. Luetscher, J. A., Kraemer, F. B. & Wilson, D. M. Prorenin and vascular complications of diabetes. Am. J. Hypertens. 2, 382–386 (1989).

    Article  CAS  Google Scholar 

  27. Wilson, D. M. & Luetscher, J. A. Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N. Engl. J. Med. 323, 1101–1106 (1990).

    Article  CAS  Google Scholar 

  28. Nguyen, G. The (pro)renin receptor: a new kid in town. Semin. Nephrol. 27, 519–523 (2007).

    Article  CAS  Google Scholar 

  29. 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  Google Scholar 

  30. 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  Google Scholar 

  31. Ingelfinger, J. R. & Dzau, V. J. Molecular biology of renal injury: Emphasis on the role of the renin-angiotensin system. J. Am. Soc. Nephrol. 2 (Suppl. 1), 9–20 (1991).

    Google Scholar 

  32. Price, D. A. et al. The paradox of the low-renin state in diabetic nephropathy. J. Am. Soc. Nephrol. 10, 2382–2391 (1999).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, 02115, MA, USA

    Norman K. Hollenberg

Authors
  1. Norman K. Hollenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares an association with Novartis as a recipient of grant/research support.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hollenberg, N. Direct renin inhibition and the kidney. Nat Rev Nephrol 6, 49–55 (2010). https://doi.org/10.1038/nrneph.2009.201

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2009.201

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