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) 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 and Structure of profibrotic and cyclooxygenase-2 independent of 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 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. nin and inhibits prorenin binding to velop proteinuria and a slowly progres- This reversible open-close conformation PRR and nonproteolytic activation,31 sive nephropathy, suggesting a direct of prorenin is called nonproteolytic activa- initially generated much interest because pathologic role of PRR in renal damage. tion and is likely to occur for prorenin it suggested there was a PRR antagonist The glomeruli of these transgenic rats bound to PRR, which then transduces en- capable of preventing diabetic nephrop- show a measurable degree of ERK1/2, zymatic activity.2,10,24 athy and cardiac fibrosis in stroke-prone p38, and c-Jun N-terminal kinase activ- If prorenin activates intracellular sig- spontaneously hypertensive rats,16,32,33,34 ity, but not EGF receptor phosphoryla- naling after binding to PRR, then prorenin thereby demonstrating a role for PRR in tion compared with controls, and renal does seem to have a function of its own. pathology. Alas, enthusiasm was rapidly levels of Ang II are normal.39 Intriguingly, there is local generation of replaced by skepticism when the in vivo A second transgenic model overex- Ang II in tissues able to synthesize prorenin data could not be reproduced.10,15,20,30 It pressing the human PRR gene exclusively that are not accessible to renin because of has subsequently been argued that the in smooth muscle cells, including vascu- the blood brain barrier, such in the brain apparent lack of effect of HRP could be lar smooth muscle cells, provides further and eye, as well as correlations between explained by the notion that HRP exerts insight into the genesis of hypertension. high prorenin levels in diabetes compli- its effect only in diseases associated with After 6 mo of age, transgenic rats develop cated by nephropathy and retinopathy and high prorenin and low renin levels be- a cardiovascular phenotype with ele- the occurrence of microvascular complica- cause HRP blocks prorenin and not re- vated systolic blood pressure (BP) and tions such as microalbuminuria.25,26 It is nin binding to PRR. In vitro results have augmentation in heart rate. Kidney func- therefore tempting to suspect these high also been discrepant. Some groups using tion is normal with increased levels of prorenin levels play a role in diabetic ne- straightforward methods such as inhibi- plasma aldosterone and a rise in the al- phropathy by stimulating PRR and induc- tion of binding of radiolabeled prorenin dosterone/renin ratio. These alterations ing profibrotic protein syntheses. and ERK activation in the presence of also progressively increase with age.40 How then is one to explain why high HRP found no inhibitory effects, even at Different levels of transgene expression prorenin levels during pregnancy are not HRP concentrations as high as 10 ␮mol/ might account for different phenotypes. associated with any poor prognostic out- L.10,15,30 Others report that HRP inhibits In the latter model, the vascular expres- comes?27 Furthermore, glomeruloscle- not only prorenin binding35 but also re- sion of the transgene is not dramatically rosis is not observed in transgenic ren-2 nin binding to recombinant PRR,36,37 or elevated in the kidney and therefore rats with inducible prorenin expression that HRP stimulates ERK1/2 by itself.38 probably not sufficient to induce pro- despite 200-fold higher prorenin levels With these latter findings, it is difficult to teinuria and glomerulosclerosis. How- after induction,28 nor is cardiac fibrosis understand how HRP could totally in- ever, in transgenic smooth muscle cells, or glomerulosclerosis observed in trans- hibit ERK1/2 phosphorylation in the PRRs show very high levels of expression genic mice overexpressing native prore- kidney of HRP-treated animals when it in lung, which increases their respiratory nin or active site-mutated prorenin.29 could itself stimulate ERK, and why HRP rate with age and might contribute to the These data argue against the notion that would not be effective in high renin rise in BP. increases in prorenin are per se a primary models when it could inhibit renin bind- Altogether, the animal models are dis- determinant of fibrotic complications. ing in vitro. appointing because, if they tend to sug- Rather, the data suggest prorenin may be In summary, much confusion re- gest a role for PRR in cardiovascular and an amplifier of fibrosis, in addition to mains concerning the mode of action of renal diseases, the message is far from high glucose, infection, inflammation, or HRP, and the discrepancy between in clear. To date, the best argument sup- immunological cytokines. vitro and in vivo data cannot be explained porting a role for PRR in hypertension is at this time. Therefore, it seems reason- the demonstration of an association be- Can We Block Renin or Prorenin able not to call HRP a “PRR blocker” un- tween PRR gene polymorphism and am- Binding to PRR with Existing til more clarity emerges. bulatory BP in Japanese men.41 Compounds? Several groups have yet to generate a The answer is clearly “no” with existing PRR-null mouse despite numerous at- Ϫ Ϫ renin inhibitors and likely “no” with a WHAT DO ANIMAL MODELS TELL tempts, possibly because PRR / em- reported PRR blocker. Studies with US ABOUT THE ROLE OF PRR IN bryonic stem cells do not form chimeras aliskiren, the available inhibitor of renin, PATHOPHYSIOLOGY? after blastocyst injection (Michael Bader, clearly show that blocking the active site personal communication). PRR deletion of renin and prorenin do not alter their Evidence that PRR is related to cardio- in C. elegans42 and zebrafish43 yields em- binding to PRR or subsequent ERK1/2 vascular disease comes from studies with bryos that die before the end of embryo- activation.10,15,30 transgenic rats overexpressing PRR. In a genesis, thus supporting an essential but

20 Journal of the American Society of Nephrology J Am Soc Nephrol 21: 18–23, 2010 www.jasn.org BRIEF REVIEW

Renin (pro)reninrenin Soluble Full length PRR PRR

Luminal side of renal intercalated cells

Transmembrane/brane/ Furin cytoplasmicmic domain of PRPRRR V-ATPase V-ATPase complexed complexed to full-length with truncated PRR PRR/M8.9

Trans golgi Nucleus

Figure 2. Intracellular processing of PRR. Part of PRR is cleaved by furin in the trans-Golgi to generate soluble PRR, which is secreted, and transmembrane PRR, which remains associated with V-ATPase. Part of PRR remains intact and is addressed to the plasma membrane. The V-ATPase may be complexed with full-length or truncated PRR. Soluble PRR binds renin and prorenin. unknown cellular function for PRR. It is tifunctional protein existing in different informative results. Finally, we know tempting to speculate this essential func- molecular forms, and even its cellular lo- very little about the structure of this pro- tion is related to the truncated form of calization is intriguing. Indeed, immu- tein because recombinant PRR is very PRR composed of the transmembrane nofluorescence studies on endoge- difficult to generate in native form. It and cytoplasmic domains of PRR that nous46,47 or transfected PRR18 show most may be wise to not put the cart before the copurify with vacuolar Hϩ-ATPase (V- of the protein is intracellular. We have horse in trying to assign functions for ATPase).44 This V-ATPase plays an es- recently shown that PRR accumulates in this new receptor before we have a clearer sential role in controlling cellular and in- the trans-Golgi, where its is cleaved by understanding of its roles in develop- tracellular vesicle pH.45 The gene coding furin to generate a 10-kD transmem- ment, physiology, and pathophysiology. this PRR is called ATP6ap2 (ATPase-as- brane/cytoplasmic fragment that likely sociated protein 2). Zebrafish embryo represents the truncated PRR, which co- mutants for V-ATPase subunits, and for purifies with the V-ATPase, and a 28-kD DISCLOSURES PRR/ATP6ap2, display similar pheno- soluble form, which is secreted into the None. types,43 suggesting a possible link be- conditioned medium of cultured cells tween the two . The demonstra- (Figure 2); more importantly, this trun- tion of a functional link between the two cated PRR is also found in plasma of hu- REFERENCES proteins was recently made by Advani mans and rats.47 The function of this sol- et al.,46 who show that PRR colocalizes uble PRR is not yet established; studies 1. Sealey JE, Glorioso N, Itskovitz J, Atlas SA, with V-ATPase in the apical villi of in- are ongoing to determine its concentra- Pitarresi TM, Preibisz JJ, Troffa C, Laragh JH: tercalated cells of the distal nephron, tion in biologic fluids and its variation in Ovarian prorenin. Clin Exp Hypertens A 9: and that inhibition of V-ATPase with different pathophysiological states. The 1435–1454, 1987 bafilomycin impairs ERK activation only known mutation in the PRR gene 2. Nguyen G, Delarue F, Burckle´ C, Bouzhir L, induced by (pro)renin. primarily affects the central nervous sys- Giller T, Sraer J-D: Pivotal role of the renin/ prorenin receptor in angiotensin II produc- tem, and animal studies indicate that tion and cellular responses to renin. J Clin PRR may not be an essential determinant Invest 109: 1417–1427, 2002 CONCLUSIONS AND of cardiovascular and renal diseases. We 3. L’Huillier N, Sharp MGF, Dunbar DR, Mullins PERSPECTIVES still know very little about its other cellu- JJ: On the relationship between the renin lar functions beyond serving as a recep- receptor and the vacuolar proton ATPase membrane sector associated protein (M8– The biology of PRR is more complex tor, and it is likely that studies in tissue- 9). In: The Local Cardiac Renin Angiotensin- than expected in several ways. It is a mul- specific PRR-null mice will give more Aldosterone System, edited by Frolich ED

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