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Renin, Prorenin, and the (Pro)renin Receptor

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The Local Cardiac Renin-Angiotensin Aldosterone System

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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 (P)RR 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.

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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. Amsterdam A, Nissen RM, Sun Z, et al. Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA. 2004;101:12792–12797.

    Article  PubMed  CAS  Google Scholar 

  2. Batenburg WW, Krop M, Garrelds IM, 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. 2007;25:2441–2453.

    Article  PubMed  CAS  Google Scholar 

  3. Burcklé C, Bader M. Prorenin and its ancient receptor. Hypertension. 2006;48:549–551.

    Article  PubMed  CAS  Google Scholar 

  4. Burcklé CA, Danser AHJ, Müller DN, et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension. 2006;47:552–556.

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  6. Danser AHJ, Deinum J. Renin, prorenin and the putative (pro)renin receptor. Hypertension. 2005;46:1069–1076.

    Article  PubMed  CAS  Google Scholar 

  7. Danser AHJ, Derkx FHM, Schalekamp MADH, et al. Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J Hypertens. 1998;16:853–862.

    Article  PubMed  CAS  Google Scholar 

  8. Feldt S, Batenburg WW, Mazak I, 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. 2008a;51:682–688.

    Article  PubMed  CAS  Google Scholar 

  9. Feldt S, Maschke U, Dechend R, et al. The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling. J Am Soc Nephrol. 2008b;19(4):743–748.

    Article  PubMed  CAS  Google Scholar 

  10. Huang Y, Border WA, Noble NA. Functional renin receptors in renal mesangial cells. Curr Hypertens Rep. 2007a;9:133–139.

    Article  PubMed  CAS  Google Scholar 

  11. Huang Y, Noble NA, Zhang J, et al. Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int. 2007b;72:45–52.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Krop M, Danser AH (2008). Circulating versus tissue renin-angiotensin system: on the origin of (pro)renin. Curr Rep. Hypertens 2008;10:112–118.

    Google Scholar 

  20. Lenz T, Sealey JE, Maack T, et al. Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys. Am J Physiol. 1991;260:R804–810.

    PubMed  CAS  Google Scholar 

  21. L’Huillier N, Sharp MGF, Dunbar DR, et al. On the relationship between the renin receptor and the vacuolar proton ATPase membrane sector associated protein (M8-9). In: Frolich ED, Re RN, eds. The Local Cardiac Renin Angiotensin-Aldosterone System. New York: Springer; 2005:17–34, Chapter 3.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Luetscher JA, Kraemer FB, Wilson DM, et al. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med. 1985;312:1412–1417.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  25. Methot D, Silversides DW, Reudelhuber TL. In vivo enzymatic assay reveals catalytic activity of the human renin precursor in tissues. Circ Res. 1999;84:1067–1072.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Nabi AH, Kageshima A, Uddin MN, et al. Binding properties of rat prorenin and renin to the recombinant rat renin/prorenin receptor prepared by a baculovirus expression system. Int J Mol Med. 2006;18:483–488.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. Prescott G, Silversides DW, Reudelhuber TL. Tissue activity of circulating prorenin. Am J Hypertens. 2002;15:280–285.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  34. Saris JJ, Derkx FHM, de Bruin RJA, et al. High-affinity prorenin binding to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin. Am J Physiol. 2001a;280:H1706–H1715.

    CAS  Google Scholar 

  35. Saris JJ, van den Eijnden MMED, Lamers JMJ, et al. Prorenin-induced myocyte proliferation: no role for intracellular angiotensin II. Hypertension. 2002;39:573–577.

    Article  PubMed  CAS  Google Scholar 

  36. Saris JJ, 't Hoen PAC, Garrelds IM, et al. Prorenin induces intracellular signalling in cardiomyocytes independently of angiotensin II. Hypertension. 2006;48:564–571.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  42. Stankovic AR, Fisher NDL, Hollenberg NK. Prorenin and angiotensin-dependent renal vasoconstriction in type 1 and type 2 diabetes. J Am Soc Nephrol. 2006;17:3293–3299.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. Takahashi H, Ichihara A, Kaneshiro Y, et al. Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade. J Am Soc Nephrol. 2007;18:2054–2061.

    Google Scholar 

  45. Tigerstedt R, Bergman PG. Niere und Kreislauf. Scand Arch Physiol. 1898;8:223–271.

    Google Scholar 

  46. van den Eijnden MMED, Saris JJ, et al. Prorenin accumulation and activation in human endothelial cells. Importance of mannose 6-phosphate receptors. Arterioscler Thromb Vasc Biol. 2001;21:911–916.

    CAS  Google Scholar 

  47. van Kesteren CAM, Danser AHJ, Derkx FHM, et al. Mannose 6-phosphate receptor-mediated internalization and activation of prorenin by cardiac cells. Hypertension. 1997;30:1389–1396.

    CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  49. Wilson DM, Luetscher JA. Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl J Med. 1990;323(16):1101–1106.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. (INSERM) Unit 833 and Collège de France, Experimental Medecine Unit, Institut de la Santé et de la Recherche Médicale, 11 place Marcelin Berthelot, 75005, Paris, France

    Genevieve Nguyen

  2. INSERM U36, College de France, 75005, Paris, France

    Aurelie Contrepas

Authors
  1. Genevieve Nguyen
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  2. Aurelie Contrepas
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Editors and Affiliations

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

    Edward D. Frohlich

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

    Richard N. Re

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Nguyen, G., Contrepas, A. (2009). Renin, Prorenin, and the (Pro)renin Receptor. In: Frohlich, E., Re, R. (eds) The Local Cardiac Renin-Angiotensin Aldosterone System. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0528-4_3

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  • DOI: https://doi.org/10.1007/978-1-4419-0528-4_3

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