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(Pro)Renin Receptor BRIEF REVIEW www.jasn.org The Biology of the (Pro)Renin Receptor Genevieve Nguyen* and Dominik N. Muller† *Institut de la Sante´ et de la Recherche Me´dicale, Paris, France; and †Max-Delbru¨ck-Center for Molecular Medicine, Berlin-Buch, Germany ABSTRACT The (pro)renin receptor (PRR) binds renin and prorenin, its proenzyme inactive BIOCHEMISTRY OF THE PRR form. Receptor-bound prorenin becomes enzymatically active and binding then activates the MAP kinases ERK1/2 and p38 pathways, leading to upregulation PRR Gene and Protein Structure of profibrotic and cyclooxygenase-2 genes independent of angiotensin II gen- In humans there is a unique gene encod- eration. These characteristics explain the interest in the potential role of PRR in ing PRR on the X chromosome at locus organ damage in diseases associated with activation of the renin-angiotensin p11.4. The messenger RNA is 2034 bp in system (RAS), in particular hypertension and diabetes. Although identification length and has a long 3Ј untranslated re- of PRR has improved our understanding of the physiology of the tissue RAS, its gion and no alternative splicing prod- role in pathology is far from clear. Transgenic animals overexpressing PRR uct.2 The protein is 350 amino acids long ubiquitously or selectively in smooth-muscle cells develop high BP or glomer- and has a single transmembrane domain ulosclerosis, and increased expression of PRR is reported in models of hyper- and a short cytoplasmic domain that has tension or kidney damage. However, definitive proof is still lacking for a role for no intrinsic kinase activity (Figure 1).2 PRR in disease, or by showing improvement of disease by tissue-specific abla- The degree of homology between hu- tion of PRR or by administration of a specific PRR antagonist. Furthermore, the man, rat, and mice PRR is about 95% for early embryonic lethality seen in PRR-null mice suggests PRR has additional the nucleotide sequence and over 80% at essential cellular functions we do not understand. the amino-acid level, indicating an ex- tremely conserved protein. A multispe- J Am Soc Nephrol 21: 18–23, 2010. doi: 10.1681/ASN.2009030300 cies protein sequence comparison re- veals homologues to the human receptor in many species, including rat, mouse, Renin is an aspartyl protease that nogaster,3,4 which express some of the chicken, frog, zebrafish, mosquito, and cleaves angiotensinogen into angioten- RAS components but not for hemody- drosophila, and in species as remote sin I, the rate-limiting reaction in the namic functions.5 This suggests PRR from humans as C. elegans and the bac- cascade generating angiotensin. The has functions unrelated to the hemo- teria, Ehrlichia chaffeensis. The highest existence of a receptor for renin and for dynamic aspects of the RAS. Further- homology is in the transmembrane and its inactive precursor, prorenin, was more, PRR also exists in truncated cytoplasmic regions, pointing to an im- postulated long ago,1 and a receptor forms that provide the potential mo- portant function for this fragment of binding renin and prorenin, termed lecular basis for these additional func- PRR.3,4,6,7 the (pro)renin receptor (PRR), was tions.4 cloned in 2002.2 The PRR is a true re- A great deal of excitement was gener- ceptor that is able to activate intracel- ated when studies indicated that prore- lular signaling, and surprisingly, PRR- nin activation might play a central role in Published online ahead of print. Publication date bound prorenin is enzymatically active diabetic nephropathy and cardiac fibro- available at www.jasn.org. as a result of a conformational change sis, and that tissue damage could be to- Correspondence: 2 Dr. Genevieve Nguyen, Institut without cleavage of the prosegment. tally prevented by blocking prorenin de la Sante´ et de la Recherche Me´dicale, (INSERM) Unlike other components of the renin- binding to PRR. Here we summarize our Unit 833 and Colle`ge de France, Experimental Me- angiotensin system (RAS), the PRR knowledge of the biochemistry of PRR, decine Unit, 11 place Marcelin Berthelot, 75005, Paris, France. Phone: ϩ33(0)1-44-27-16-89; Fax: gene is highly conserved among spe- discuss the variations of PRR in several ϩ33(0)1-44-27-16 91; E-mail: genevieve.nguyen@ cies, and PRR orthologues are found in disease models, and report data support- college-de-france.fr species as far from mammals as Caeno- ing a role for PRR in embryologic devel- Copyright ᮊ 2010 by the American Society of rhabditis elegans and Drospohila mela- opment and RAS-independent actions. Nephrology 18 ISSN : 1046-6673/2101-18 J Am Soc Nephrol 21: 18–23, 2010 www.jasn.org BRIEF REVIEW Figure 1. Schematic organization of PRR protein (the indicated 28 kDa molecular weight was determined by SDS-PAGE, and 35 kDa and 8.9 kDa were estimated based on the amino-acid sequence). Characteristics and Consequences scription factor that downregulates the ex- naling only needs minimal binding and of Renin and of Prorenin Binding pression of PRR, thereby providing a ERK1/2 activation is observed with (pro)- The PRR receptor specifically binds re- feedback mechanism by which (pro)renin renin concentrations as low as 1 pmol/ nin and prorenin (collectively named controls the amount of its own receptor.8,18 L.12 The relevance of ERK1/2 activation (pro)renin when used interchangeably) However, the negative feedback mecha- in animal models will be discussed later with two important consequences: pro- nism has been described mostly in vitro, in this review. But there is at least one renin, the inactive proenzyme form of and in vivo evidence is scarce.19 For exam- physiologic situation in which activation renin, becomes enzymatically active by a ple, Krebs et al.20 used a model of severe of ERK1/2 by PRR is essential, namely conformational change that does not re- renal ischemia to demonstrate that isch- during brain development, as suggested quire cleavage of the prosegment, and emia leads to a pronounced increase in by X-linked mental retardation and epi- PRR activation triggers intracellular sig- renal renin and prorenin, but PRR is lepsy observed in a family in which link- naling pathways. Cross-linking2 as well increased rather than downregulated, age analysis and mutation screening as co-immunoprecipitation8 studies in- underlining that caution is always identified only one single mutation in dicate that PRR functions as a dimer on needed when trying to apply in vitro the PRR gene. Studies on immortalized plasma membranes. The affinity of signaling data to every in vivo patho- lymphocytes of one patient show the PRR for (pro)renin is in the nanomolar logic situation. mutation is responsible for the absence range.2,9,10 The sequences of the of ERK1/2 phosphorylation by renin.22 ectodomain responsible for the inter- Are Binding of (Pro)Renin to PRR action with (pro)renin have not yet and ERK Activation Relevant In Binding and Nonproteolytic been determined by structure-function Vivo? Activation of Receptor-Bound studies. As discussed by Campbell,21 the plasma Prorenin: Why Is It So Exciting? The binding of (pro)renin triggers in- concentration of renin and prorenin is in Prorenin is the inactive proenzyme tracellular signaling and the activation of the picomolar range and the affinity of form of renin and yet its concentration the mitogen-activated protein (MAP) ki- (pro)renin for PRR is in the nanomolar in human plasma is 7- to 9-fold higher nases ERK1/2, leading to upregulation of range. Therefore, one would expect very that of renin. Prorenin is inactive be- TGF␤1, PAI1, collagens, fibronectin,11,12,13 low receptor occupancy (approximately cause a 43-amino acid prosegment cov- and cyclooxygenase-2,14 independent of 1%), suggesting that local Ang II genera- ers the enzymatic cleft and is activated angiotensin (Ang) II generation and EGF tion dependent on the uptake of circulat- in a proteolytic or nonproteolytic man- receptor transactivation.15 Definitive proof ing (pro)renin is negligible. However, in ner.23 Proteolytic activation is due to that ERK1/2 phosphorylation is mediated organs and tissues able to synthesize re- the removal of the propeptide by an by (pro)renin binding to PRR is provided nin and prorenin, such as kidneys, ova- unidentified proconvertase, for which by the disappearance of this response after ries, placenta, testes, adrenal glands, and the process is irreversible and takes knockdown of PRR expression by transfec- retina, the role of (pro)renin in Ang II place only in the renin-producing cells tion with small-inhibiting RNAs.11 Addi- generation could be substantial. Unfor- of the juxtaglomerular apparatus dur- tionally, PRR activation also triggers a tunately, studies on PRR occupancy in ing normal physiology. In plasma, MAP kinase p38-heat shock protein 27 these tissues are not available and only there is a dynamic equilibrium be- cascade16,17 and the PI3K-p85 pathway.8 tissue-specific null animals would help tween 2% of prorenin in an open, ac- The latter results in the nuclear transloca- clarify this issue. tive form and 98% in closed, inactive tion of the promyelocytic zinc finger tran- On the other hand, intracellular sig- conformation. Opening the proseg- J Am Soc Nephrol 21: 18–23, 2010 The (Pro)Renin Receptor 19 BRIEF REVIEW www.jasn.org ment in vitro is achieved by exposure to low The description of a peptide called study where the human PRR is overex- pH (pH ϭ 3.0) or cold temperatures “handle region peptide (HRP),” which pressed ubiquitously in transgenic rats, (4°C)23 and is reversed by neutralizing the mimics part of the prosegment of prore- the rats remain normotensive but de- pH or increasing the temperature to 37°C.
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