Skip to main content
SpringerLink
Log in
Book cover

Renin Angiotensin System and Cardiovascular Disease pp 15–24Cite as

Renin, Prorenin, and the (Pro)Renin Receptor

  • Chapter
  • First Online:

Part of the book series: Contemporary Cardiology ((CONCARD))

Abstract

The discovery of a receptor for renin and for its inactive precursor prorenin, and the introduction of renin inhibitors in therapeutic, has renewed the interest for the physiology of the renin angiotensin system (RAS) and has brought prorenin back in the spotlight. The receptor known as renin for (Pro)Renin Receptor binds both renin and prorenin, and binding triggers intracellular signaling involving the MAP kinases ERK1/2 and p38. The MAP kinases activation in turn upregulates the expression of profibrotic genes, potentially leading to fibrosis, growth, and remodeling. Simultaneously, binding of renin to (P)RR increases its angiotensin I-generating activity, whereas binding of prorenin induces the inactive prorenin to become enzymatically active. These biochemical characteristics of (pro)renin binding to (P)RR allow to distinguish two aspects for the new (pro)renin/(P)RR system, an angiotensin-independent function related to the intracellular signaling and its downstream effects and an angiotensin-dependent aspect related to the increased generation of angiotensin I on the cell surface. Ongoing experimental studies should now determine which of the two aspects is the most important in pathological situations.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

(pro)renin::

designate renin and prorenin

AOG::

angiotensinogen

Ang I and Ang II::

angiotensin I and angiotensin II

ACE::

angiotensin-converting enzyme

HRP::

handle region peptide

(P)RRB::

(pro)renin receptor blocker

References

  1. Danser, A.H.J., Derkx, F.H.M., Schalekamp, M.A.D.H., et al. (1998). 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.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  3. Danser, A.H.J., and Deinum, J. (2005). Renin, prorenin and the putative (pro)renin receptor. Hypertension 46, 1069–1076.

    Article  CAS  PubMed  Google Scholar 

  4. Luetscher, J.A., Kraemer, F.B., Wilson, D.M., et al. (1985). Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med 312, 1412–1417.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  6. Stankovic, A.R., Fisher, N.D.L., and Hollenberg, N.K. (2006). Prorenin and angiotensin-dependent renal vasoconstriction in type 1 and type 2 diabetes. J Am Soc Nephrol 17, 3293–3299.

    Article  CAS  PubMed  Google Scholar 

  7. Lenz, T., Sealey, J.E., Maack, T., et al. (1991). Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys. Am J Physiol 260, R804–R810.

    CAS  PubMed  Google Scholar 

  8. Véniant, M., Ménard, J., Bruneval, P., et al. (1996). Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 98, 1966–1970.

    Article  PubMed  Google Scholar 

  9. Prescott, G., Silversides, D.W., and Reudelhuber, T.L. (2002). Tissue activity of circulating prorenin. Am J Hypertens 15, 280–285.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Methot, D., Silversides, D.W., and Reudelhuber, T.L. (1999). In vivo enzymatic assay reveals catalytic activity of the human renin precursor in tissues. Circ Res 84, 1067–1072.

    CAS  PubMed  Google Scholar 

  12. Maru, I., Ohta, Y., Murata, K., et al. (1996). Molecular cloning and identification of N-acyl-D-glucosamine 2-epimerase from porcine kidney as a renin-binding protein. J Biol Chem 271, 16294–16299.

    Article  CAS  PubMed  Google Scholar 

  13. van Kesteren, C.A.M., Danser, A.H.J., Derkx, F.H.M., et al. (1997). Mannose 6-phosphate receptor-mediated internalization and activation of prorenin by cardiac cells. Hypertension 30, 1389–1396.

    PubMed  Google Scholar 

  14. Saris, J.J., Derkx, F.H.M., de Bruin, R.J.A., et al. (2001a). High-affinity prorenin binding to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin. Am J Physiol 280, H1706–H1715.

    CAS  Google Scholar 

  15. van den Eijnden, M.M.E.D., Saris, J.J., et al. (2001). Prorenin accumulation and activation in human endothelial cells. Importance of mannose 6-phosphate receptors. Arterioscler Thromb Vasc Biol 21, 911–916.

    PubMed  Google Scholar 

  16. Schmitz, C., Gotthardt, M., Hinderlich, S., et al. (2000). Normal blood pressure and plasma renin activity in mice lacking the renin-binding protein, a cellular renin inhibitor. J Biol Chem 275, 15357–15362.

    Article  CAS  PubMed  Google Scholar 

  17. Saris, J.J., van den Eijnden, M.M.E.D., Lamers, J.M.J., et al. (2002). Prorenin-induced myocyte proliferation: no role for intracellular angiotensin II. Hypertension 39, 573–577.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Huang, Y., Noble, N.A., Zhang, J., Xu, C., et al. (2007b). Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int 72, 45–52.

    Article  CAS  PubMed  Google Scholar 

  21. Sakoda, M., Ichihara, A., Kaneshiro, Y., et al. (2007). (Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells. Hypertens Res 30, 1139–1146.

    Article  CAS  PubMed  Google Scholar 

  22. Feldt, S., Batenburg, W.W., Mazak, I., et al. (2008a). 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.

    Article  CAS  PubMed  Google Scholar 

  23. Huang, Y., Border, W.A., and Noble, N.A. (2007a). Functional renin receptors in renal mesangial cells. Curr Hypertens Rep 9, 133–139.

    Article  CAS  PubMed  Google Scholar 

  24. Saris, J.J., ’t Hoen, P.A.C., Garrelds, I.M., et al. (2006). Prorenin induces intracellular signalling in cardiomyocytes independently of angiotensin II. Hypertension 48, 564–571.

    Article  CAS  PubMed  Google Scholar 

  25. Schefe, J.H., Menk, M., Reinemund, J., et al. (2006). A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res 99, 1355–1366.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Batenburg, W.W., Krop, M., and Garrelds, I.M., et al. (2007). 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.

    Article  CAS  PubMed  Google Scholar 

  28. Nabi, A.H., Kageshina, A., Uddin, M.N., Nakagawa, T. ,et al. (2006) Binding properties of rat prorein and renin to recombinant rat renin prorein receptor prepared by a baculovir expression system. Int. I Mol Med 18, 483–488

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Ichihara, A., Kaneshiro, Y., Takemitsu, T., et al. (2006a). Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 47, 894–900.

    Article  CAS  PubMed  Google Scholar 

  32. Satofuka S, Ichihara A, Nagai N, et al. (2006). Suppression of ocular inflammation in endotoxin-induced uveitis by inhibiting nonproteolytic activation of prorenin. Invest Ophthalmol Vis Sci 47, 2686–2692.

    Article  PubMed  Google Scholar 

  33. Müller, D.N., Klanke, B., Feldt, S., et al. (2008). (Pro)renin receptor peptide inhibitor “handle-region” peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. Hypertension 51, 676–681.

    Article  PubMed  CAS  Google Scholar 

  34. Burcklé, C.A., Danser, A.H.J., Müller, D.N., et al. (2006). Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension 47, 552–556.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Siragy, H.M., and Huang, J. (2008) Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp Physiol 93(5), 709–714

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Burcklé, C., and Bader, M. (2006). Prorenin and its ancient receptor. Hypertension 48, 549–551.

    Article  PubMed  CAS  Google Scholar 

  41. Ludwig, J., Kerscher, S., Brandt, U., et al. (1998). Identification and characterization of a novel 9.2-kDa membrane sector-associated protein of vacuolar proton-ATPase from chromaffin granules. J Biol Chem 273, 10939–10947.

    Article  CAS  PubMed  Google Scholar 

  42. Nishi, T., and Forgac, M. (2002). The vacuolar (H+)-ATPases–nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 3, 94–103.

    Article  CAS  PubMed  Google Scholar 

  43. Amsterdam, A., Nissen, R.M., Sun, Z., et al. (2004). Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA 101, 12792–12797.

    Article  CAS  PubMed  Google Scholar 

  44. Contrepas, A., Praizovic, N., Duong Van Huyen, J.P., et al. (2007). Expression of (pro)renin receptor in mouse embryonic and newborn kidney and proliferative effect of soluble (P)RR on mesangial cells. Hypertension 50, e145 (Abstract).

    Google Scholar 

  45. L’Huillier, N., Sharp, M.G.F., Dunbar, D.R., et al. (2006). On the relationship between the renin receptor and the vacuolar proton ATPase membrane sector associated protein (M8-9). In: E.D. Frolich and R.N. Re. (eds.) The Local Cardiac Renin Angiotensin-Aldosterone System. Chapter 3. Springer, 233 spring street, new york NY10013, USA, pp. 17–34.

  46. Tigerstedt, R., and Bergman, P.G. (1898). Niere und Kreislauf. Scand Arch Physiol 8, 223–271.

    Google Scholar 

  47. Nguyen, G., and Danser, A.H. (2008) Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. Exp Physiol 93, 557–563.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut de la Santé et de la Recherche Médicale, París, France

    Genevieve Nguyen MD, PhD

  2. Experimental Medecine Unit, Institut de la Santé et de la Recherche Médicale and Collège de France, Paris, France

    Aurelie Contrepas BS

Authors
  1. Genevieve Nguyen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aurelie Contrepas BS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Genevieve Nguyen MD, PhD .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, University of Puerto Rico, San Juan, 00936, U.S.A.

    Walmor C. DeMello

  2. Ochsner Clinic Foundation, Jefferson Highway 1514 , New Orleans, 70121, U.S.A.

    Edward D. Frohlich

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Nguyen, G., Contrepas, A. (2009). Renin, Prorenin, and the (Pro)Renin Receptor. In: DeMello, W., Frohlich, E. (eds) Renin Angiotensin System and Cardiovascular Disease. Contemporary Cardiology. Humana Press. https://doi.org/10.1007/978-1-60761-186-8_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-186-8_3

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-185-1

  • Online ISBN: 978-1-60761-186-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation