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The (Pro)Renin Receptor: a New Kid in Town

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The (Pro)Renin Receptor: a New Kid in Town The (Pro)Renin Receptor: A New Kid in Town Geneviève Nguyen, MD, PhD Summary: Renin inhibitors are now available in therapeutic doses and it is accepted that they decrease blood pressure as efficiently as the classic inhibitors of the renin-angiotensin system (RAS): angiotensin converting enzyme inhibitors and angiotensin II–receptor blockers (ARBs). One major issue will be to know how, beyond the normalization of blood pressure, renin inhibitors (RIs) will compare with angiotensin converting enzyme inhibitors and ARBs for their ability to protect the organs against the tissue damage associated with overactivation of the RAS. The mechanism(s) of tissue protection may involve the inhibition of a direct cellular effect of renin and prorenin mediated by the (pro)renin receptor ([P]RR). This review updates the recent findings on (P)RR; its role in hypertension, cardiac fibrosis, diabetic nephropathy, and retinopathy; and the effects of a putative (P)RR antagonist. Semin Nephrol 27:519-523 © 2007 Elsevier Inc. All rights reserved. Keywords: Renin-angiotensin system, renin, prorenin, and (pro)renin receptor he renin-angiotensin system (RAS) is be- THE (P)RR coming more and more complex. In 3 The (P)RR receptor is a 350-amino acid protein Tdecades, the classic intravascular system with no homology with any known protein. aimed at the generation of angiotensin II (Ang The primary structure analysis showed the ex- II), considered a unique biologically active pep- istence of the following: (1) a signal peptide, tide, has been enriched with new enzymes, which is indicative of a secreted protein; (2) a such as angiotensin converting enzyme 2 and large ectodomain responsible for renin and pro- chymase, and new receptors such as for angio- renin binding; (3) a single transmembrane do- tensin IV and for (pro)renin ([pro]renin refers main; and (4) a short cytoplasmic domain in- 1 to renin and prorenin collectively). These dis- volved in the intracellular signaling. coveries will affect our comprehension of the Renin and prorenin bind equally well to RAS profoundly, but they also may help to im- (P)RR and their binding has 2 fundamental ef- prove the use of RAS blockers, which are fects: (1) binding increases renin catalytic activ- among the most widely used drugs. Several ity, remarkably, allowing prorenin to become recent reviews have discussed (pro)renin bind- active; and (2) binding triggers the activation of 2-4 ing proteins, but this review focuses on the mitogen-activated protein kinases p44/p42 or specific receptor of (pro)renin, called the extracellular regulated kinases 1/2 (ERK1/2).5 (pro)renin receptor ([P]RR). We mainly discuss the role of (P)RR in prorenin activation and the effects of the putative (P)RR antagonist in dia- Increased Catalytic Activity betic nephropathy, cardiac fibrosis, and endo- of Receptor-Bound Renin and Prorenin toxin-induced uveitis. One fundamental property of (P)RR is that its existence now provides a functional role for Institut National de la Santé et de la Recherche Médicale, INSERM Unit 36, and prorenin, the proenzyme inactive form of re- Collège de France, Unit of Experimental Medicine, Paris, France. nin. This functional role for prorenin was sus- Address reprint requests to Geneviève Nguyen, MD, PhD, Institut de la Santé 6-8 et de la Recherche Médicale, INSERM Unit 36, and Collège de France, pected long ago. Prorenin is released consti- Experimental Medecine Unit, 11 Place Marcelin Berthelot, 75005, Paris, tutively from the kidney and its concentration France. E-mail: [email protected] 0270-9295/07/$ - see front matter in plasma is 10-fold higher than the concentra- 9 © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2007.07.004 tion of renin. Unlike other proteases, prorenin Seminars in Nephrology, Vol 27, No 5, September 2007, pp 519-523 519 520 G. Nguyen does not undergo self-activation and the unique specifically the nonproteolytically activated maturation site of prorenin into renin is the prorenin and not the native prorenin or mature myoepithelioid cell of the juxtaglomerular ap- renin. paratus where the pro-segment of renin is In diabetic rats, HR peptide infusion normal- cleaved-off by a still unknown pro-convertase. ized renal angiotensin I and angiotensin II levels This gain of activity of receptor-bound prorenin that retuned to values comparable with those of is attributed to a conformational change, pro- control animals, whereas plasma angiotensins voking the loosening of the pro-segment and were not modified. The proteinuria was nor- making the enzymatic cleft accessible to angio- malized and glomerulosclerosis was inhibited tensinogen. This phenomenon is reversible by completely.14 eluting prorenin from the receptor and is called In stroke-prone spontaneously hypertensive nonproteolytic activation, in contrast to the rats (SHRsp), HR peptide infusion was able to proteolytic activation of prorenin caused by prevent cardiac fibrosis as a result of increased cleavage of the pro-segment to produce the expression of cardiac (P)RR.15 Furthermore, HR mature renin, which is an irreversible process. peptide also could prevent renal damage and The increased catalytic activity by a nonproteo- normalized transforming growth factor-␤1 lytic activation of receptor-bound prorenin was (TGF-␤1) in SHRsp.16 confirmed using recombinant rat (P)RR and But the most convincing argument of the prorenin.10 pathogenic role of prorenin nonproteolytic ac- The crystal structure of renin was established tivation and of (P)RR activation came from the some time ago,11 but there is no crystal structure study of the protective effect of HR peptide in of prorenin, and therefore of the pro-segment, diabetic angiotensin II type 1a receptor–defi- available so far. However, when comparing the cient mice. Not only did HR peptide attenuate pro-segment of prorenin with the pro-segment of the development of proteinuria and glomerulo- pepsinogen, another aspartate protease, one can sclerosis, but it also inhibited the increased identify 2 leucine residues in the sequence ERK1/2 of p38 and of cϭJun Nϭterminal ki- R10ILL13KKMPSV19 of the pro-segment. The pro- nase (JnK) activation in the diabetic kidney, segment of prorenin acts as a trapdoor that confirming once more that (P)RR can exert a covers the active site. In this trapdoor, leucine pathologic role independently of Ang II gener- 13 (L13), which is extremely conserved among ation. Most importantly, the renal protection aspartyl-protease proenzyme and among spe- achieved with HR peptide was superior to that cies, plays a crucial role in keeping the trapdoor of an angiotensin converting enzyme inhibitor 18 closed (Daniel Bur, personal communication). in diabetic wild-type animals. Mutation of L13 results in an unstable pro-seg- To summarize, the results of these experi- ment and spontaneously active prorenin.12 By mental studies have raised 2 interesting hypoth- using an antibody to this region that likely re- eses: (1) that prorenin was the main ligand of acted with the central L13, Suzuki et al13 ob- (P)RR in vivo and (2) that HR peptide may act as tained a nonproteolytic activation of prorenin an antagonist of (P)RR. and called this region the handle region (HR), However, many questions still remain unan- using an analogy for the handle of a picnic swered. basket. By using the HR peptide, Ichihara et al14-16 What is the Exact subsequently showed that infusion of HR pep- Mechanism of Action of HR Peptide? tide was able to inhibit cardiac and renal dam- Although the effect of HR peptide was impres- age induced by hypertension and diabetes, and sive in vivo, its mechanism of action was never to provide protection from uveitis induced by shown. Indeed, it was reported that HR peptide lipopolysaccharide.17 In all these studies the may block the binding of prorenin to Chinese investigators showed an increase of nonproteo- hamster ovary (CHO) cells overexpressing lytic activation of prorenin by immunohisto- (P)RR, however, no data were shown.18 In ad- chemistry using an antibody that recognizes dition, there was a mention that HR peptide The (pro)renin receptor 521 behaves similar to a partial agonist of (P)RR and trations, renin could induce an increase of was able to activate ERK1/2,19 and this is in TGF-␤1 expression in rat mesangial cells that in complete contradiction with the report that HR turn up-regulates the expression of other profi- peptide infusion inhibited ERK1/2, p38, and brotic molecules such as plasminogen activator JnK activation in the kidney of diabetic mice.18 inhibitor 1, fibronectin, and collagen I. This Much work is needed and data should be increase of TGF-␤1 was abolished when cells provided that show the binding of HR peptide were transfected with small inhibiting RNA to the (P)RR and the inhibition of (pro)renin (siRNA) targeting rat (P)RR, thereby proving binding by HR peptide before the HR peptide is unequivocally that this effect of renin was me- called a (P)RR antagonist. diated by the (pro)renin receptor. Then Huang et al25 confirmed that the up-regulation of the What Would be the Effect expression of TGF-␤ and other profibrotic mol- of HR Peptide on Situations ecules was indeed caused by ERK 1/2 activa- Associated With Increased Renin? tion. In addition, the activation of (P)RR also Recent reports of rats treated with angiotensin was shown to induce mitogen-activated protein converting inhibitor and on a low-salt diet sug- kinase p38 and heat shock protein (Hsp)-27 gested that the receptor was down-regulated in phosphorylation
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