[Frontiers in Bioscience E5, 500-508, January 1, 2013]

(Pro)renin receptor: subcellular localizations and functions

Gabin Sihn1, Celine Burckle2, Anthony Rousselle1, Tatiana Reimer1, Michael Bader1

1Max-Delbrueck-Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, D-13125 Berlin-Buch, Germany, 2INSERM U983, Tour Lavoisier, Hopital Necker-Enfants Malades, 149 rue de Sevres, Paris, France


1. Abstract
2. Introduction
3. (P)RR structure and subcellular localization
4. Role of (P)RR as a cell surface receptor?
5. Role of (P)RR in intracellular vesicle trafficking?
6. Conclusion
7. Acknowledgement
8. References


Since its first report in 1996, the concept of the so-called (Pro)renin receptor ((P)RR/ATP6ap2) has dramactically evolved from a receptor mediating cellular effects of (pro)renin, to a protein with more basic and potentially essential intracellular functions. Among the arguments urging to reconsider the role of (P)RR was the observation that its localization appears mainly intracellular, although this does not preclude potential functions at the cell surface. However, despite about 10 years of research boosted by the generation of genetically modified animal models, the basic mechanisms of action of this protein at the cellular level remain elusive. This review aims at discussing the functions described for (P)RR in relation to its subcellular localization(s).


In the old-fashioned view of blood pressure control in vertebrates, the renin-angiotensin system (RAS) was conceived as a circulating regulatory system. Renin, the enzyme controlling the rate-limiting degradation of angiotensinogen into vasoactive peptides, was believed to have a biological significance only in its proteolytically activated form. Its precursor prorenin was considered to be devoid of any function. However, these two dogmas have recently been challenged by the description of so-called tissular/local RAS (which refer to the presence of some or all components of the RAS within tissues, where they can initiate actions at the cellular level), as well as the discovery of new components with unexpected functions (1). In this regard, the discovery of the (pro)renin receptor ((P)RR) epitomized this modernized conception of the RAS. Described for the first time in 1996 for its ability to bind renin at the surface of mesangial cells in vitro and later reported to have high affinity for prorenin as well (2, 3), the (P)RR stood out from the other (pro)renin binding sites described before (for review, see (4)) by its properties of a real receptor. Upon binding of (pro)renin, the (P)RR did not internalize (3, 5) but rather induced a dual cellular response by 1) a non-proteolytic, catalytic activation of both renin forms for the angiotensinogen-to-angiotensin I conversion, and 2) an angiotensin-independent, intracellular signaling pathway via Mitogen-activated protein kinase (MAPK) phosphorylation (3). Thus, it provided the field with an unexpected functional relevance for prorenin, and a novel mechanism for the actions of (pro)renin at the molecular level.

However, accumulating evidence suggests the possibility that this function as a receptor may actually be secondary to more fundamental cellular functions. First, it has to be remembered that even before its first cloning (3), the (P)RR had been identified as a possible accessory subunit of the multi-protein complex Vacuolar H+-ATPase (V-ATPase). Hence (P)RR got an additional denomination, ATPase, H+ transporting, lysosomal accessory protein 2 (Atp6ap2) (6). In support of a functional link between them, zebrafish mutants for atp6ap2 phenocopy those for various subunits of the V-ATPase (7, 8) (G. Sihn, unpublished data). On the contrary, the comparison of the gene deletions for (P)RR and the various RAS components in the mouse failed to show any similarity, thus not confirming a functional link between (P)RR and (pro)renin in vivo (see chapter 4). Secondly, it has become evident that (P)RR mainly resides within intracellular organelles, and the proportion of the protein at the cell surface is a matter of debate. In the absence of (pro)renin internalization, the relevance of its function as a cell surface receptor needs to be re-evaluated, and other intracellular functions are now being considered (see below).

Nevertheless, with regards to the increasing amount of research devoted to (P)RR over the past ten years, it is surprising that the actual subcellular distribution of this protein has not been clarified yet. This may be a key issue as it could confirm or invalidate some of the cellular mechanisms of action described so far. This paper aims at summarizing the literature and presenting novel data on the subcellular localization of (P)RR and its implications concerning the functions of the protein.


(Pro)renin receptor ((P)RR/ATP6ap2) was discovered in human mesangial cells in vitro and cloned in 2002 (3). The human ATP6AP2 gene, located on the X chromosome at locus p11.4, codes for a protein with 350-amino acids and a predicted mass of around 37 kDa. Analysis of the amino acid sequence revealed two hydrophobic domains predictive of a signal peptide and a transmembrane domain and suggested a type I-transmembrane protein. We used proteinase K digestion assays on membrane preparations in vitro (Figure 1) and confirmed the type I structure with an N-terminal signal peptide, an extracellular domain likely to be involved in (pro)renin binding, a single transmembrane domain and a short cytoplasmic domain. In addition, shedding events have been described, which allow the generation of shorter forms upon the action of the proteases furin and/or ADAM19 within the Golgi/trans-Golgi apparatus (9, 10): 1) a soluble (P)RR of 28-29 kDa corresponding to the first 278 amino acids, and 2) a segment including the transmembrane domain and the C-terminal tail and roughly corresponding to the so-called M8-9 fragment (see below). So far, the question of the respective functions of these shorter forms as well as whether they are trafficked and localized in a similar way in the cell, is still unclear (see below).

In their seminal articles, Nguyen et al. provided evidence for cell surface expression of (P)RR (2, 3). When transfecting human fetal mesangial cell lines with the (P)RR cDNA in vitro, they were able to localize the protein at the plasma membrane. Consistent with its role as a receptor, binding of (pro)renin was reported to trigger cellular effects such as hyperplasia and fibrinolytic activity (2), as well as angiotensin-dependent and -independent molecular responses (3). (P)RR at the plasma membrane has also been reported in other cell types, like in primary neurons in culture (11) or A-type intercalated cells of the rat kidney collecting ducts, which express it in the microvilli at their apical surface (12).

However, accumulating evidence suggests localization and/or functions within intracellular compartments: 1) the M8-9 fragment was localized in the membrane of chromaffin granules, an organelle related to synaptic vesicle (6), and in synaptic vesicles themselves (13); and 2) the full-length (P)RR appeared to be identical to the yet unpublished protein CAPER (Genbank entry AY038990) which stands for endoplasmic reticulum localized type I transmembrane adaptor precursor C, thus suggesting location in the endoplasmic reticulum (ER).

At the molecular level, examination of the amino acid sequence revealed two theoretical targeting signals within the cytoplasmic tail, both compatible with such locations: a tyrosin-based motif Y335DSI and a C-terminal dibasic motif (K346IRMD) (14). The tyrosine-based sorting signal, YxxØ (where x is any amino acid, and Ø is a large hydrophobic amino acid), is used for protein sorting to endosomes and lysosomes through interaction with adaptor protein (AP) complexes (15). The final C-terminal motif is reminiscent of the conventional dibasic signals K(x)Kxx and R(x)Rxx and is optimally localized for constituting an ER retention/retrieval signal. However it is an uncommon sequence in vertebrates. Nevertheless, the replacement of the K(x)Rxx sequence by R(x)Rxx in a tagged version of the full length receptor, was shown to affect its main localization in the ER, with a relocation partially overlapping the lysosomal compartment, suggesting that the KIRMD motif is functional (16). Correspondingly, a fusion protein consisting of the human (P)RR with a flag inserted between the signal peptide and the extracellular domain and expressed in insect cells, was also reported to localize in the ER mainly (17). Very interestingly, in both studies, shorter forms of (P)RR presented distribution patterns that differed from the full length receptor. A tagged form of the M8-9 segment had a predominant lysosomal homing (16). On the contrary, a short form lacking the transmembrane and the intracellular domains displayed a punctuate pattern within cell organelles which poorly overlapped the Golgi complex or the lysosomes (17). The implication of these observations will be further discussed at the end of the chapter.

That (P)RR is mainly localized in the ER is also supported by data obtained in our group. We studied the subcellular distribution of (P)RR in human embryonic kidney cells using a (P)RR fusion protein labeled with the green fluorescent protein (GFP) at its N-terminus (Figure 2). Immunofluorescence with various organelle markers showed a colocalization of the tagged protein with the ER marker TRAPα (Figure 2D-F) but no or little colocalization with Golgi (Mannosidase II, Figure 2G-I) and lysosomal/endolysosomal (Figure 2J-L) markers.

In addition to the ER, other intracellular localizations have also been reported in the literature. In A-type intercalated cells of the kidney collecting duct, Advani et al. could detect (P)RR in structures reminiscent of the Golgi apparatus, where it colocalized with the B1/2 subunit of the V-ATPase as revealed by confocal immunofluorescence (12). Cousin et al., while describing the cleavage of the native (P)RR by furin in human glomerular epithelial cells, described the full length protein to be mainly in the trans-Golgi, where the cleavage by furin was reportedly taking place (9). Yoshikawa et al., while describing the cleavage of a tagged-(P)RR by ADAM19 in vascular smooth muscle cells, reported a main localization in the Golgi and the ER and confirmed that the generation of shorter forms of (P)RR was taking place in the Golgi (10).

Such discrepancies about (P)RR subcellular distribution could be attributed at least in part, to differences between the cell types analyzed in these various studies. In addition, it is important to underline that most of these data have been obtained with histo/cytochemical techniques, which could also account for part of the differences due to the drawbacks of these methods. Indeed, immunochemistry/fluorescence is highly dependent on the reliability of the antibodies as well as on the epitope they target. In addition, overexpression of constructs in cells after transient transfection may lead to missorting of the encoded proteins. Finally, addition of tags at both the N- or C-terminus of a protein (such as the construct used in Figure 2) may lead to protein misfolding as well as affect sequences important for protein trafficking (see chapter 1), thereby further increasing the risk of missorting.

We tackled this problem by using a biochemical approach with endogenously expressed untagged (P)RR. We first performed cell surface biotinylation on mouse embryonic stem cells in vitro (Figure 3A). In this technique, cell surface proteins are biotinylated and, after cell lysis, are purified on a streptavidin column (bound fraction) while the intracellular proteins are recovered in the eluate. Using a specific antibody against (P)RR, we were able to show that only a small fraction of the total cellular content of (P)RR was in the bound fraction, the vast majority being found in the eluate. By using knockout embryonic stem (ES) cells as control we could verify that the 39kDa band in the western blots is indeed (P)RR. These data provide strong support to other publications describing a mainly intracellular localization for (P)RR (16, 17). However, it is important to stress that the anti-(P)RR antibody used in this experiment has been raised against the N-terminal part of the protein, which is subject to withdrawal upon shedding by proteases like furin and/or ADAM19 (9, 10). As the cell supernatant was not included in our analysis, it is likely that at least part of the receptors at the cell surface could not be detected with our antibody. Nevertheless, a small but detectable portion of full-length (P)RR appears to reside on the cell surface, substantiating its postulated receptor function. We then examined (P)RR location using the percoll gradient fractionation method with extracts from ES cells and kidney of mice. (P)RR was indeed highly concentrated in a mixed membrane compartment comprising ER and endosomes, but absent in the highest density fraction corresponding to lysosomes (Figure 3B-C). Moreover, an additional smaller band detected in the ER-endosome fraction of kidney preparations suggested processing of (P)RR in tissues (Figure 3C). Similar subcellular distribution and processing was also observed in brain extracts (data not shown). Together with our immunofluorescence results (Figure 2), these data support a predominant intracellular localization, and favor the ER as the main homing compartment of (P)RR, in accordance to the abovementioned literature and the CAPER denomination.

However as mentioned above, shorter forms of (P)RR distribute in a different manner as the full length form (16, 17). Notably, the M8-9 segment reportedly locates preferentially to the lysosomal compartment, despite the presence of the ER-retention signal KIRMD (16). This may suggest that this motif is necessary, although not sufficient, for targeting the receptor to the ER. The limitation due to the use of tagged proteins in these 2 studies needs to be kept in mind. Nonetheless, they give some credit to the hypothesis that the various forms and/or domains of (P)RR may have different subcellular distributions and/or functions.


Can the functions described for (P)RR to date help to define in a more precise manner its subcellular localization? Above all, it is important to underline that although several biological functions have been proposed, most of them need further confirmation and it remains to be determined whether they reflect the versatility of a multi-functional protein (in regard to the hypothesis that the different domains may have different functions and localizations), or whether they represent diverse outcomes of one single molecular mechanism.

Already the original description by Nguyen et al. shaped the concept of a cell surface receptor. According to the authors, (P)RR was able to bind (pro)renin at the cell surface in vitro, and to mediate cellular responses by at least two mechanisms: a non-proteolytic activation of (pro)renin leading to increased generation of angiotensin peptides, and the induction of an angiotensin-independent intracellular signaling through ERK1/2 phosphorylation (2, 3). The finding that (pro)renin was not internalized upon binding (3, 5), suggested that (P)RR function as a receptor was taking place at the cell surface. Alternative pathways in response to renin binding were also reported: the group of Unger proposed that upon activation by renin, (P)RR interacts with the Promyelocytic leukaemia zinc finger protein 1 (PLZF) (identified in a yeast 2-hybrid screening) by its short cytoplasmic tail and stimulates PLZF translocation into the nucleus where it can modulate transcriptional activity (16). It is however not clear whether (pro)renin binding takes place at the cell surface as they described (P)RR to be mainly intracellular. Also, Advani et al., in an attempt to reconcile both aspects of the protein as a receptor and an accessory subunit of the V-ATPase, proposed a functional link between (P)RR and the proton pump: by either knocking down (P)RR expression or blocking the V-ATPase function with bafilomycin in MDCK cells in vitro, they were able to impair the intracellular induction of ERK 1/2 phosphorylation upon (pro)renin binding (12). Yet, their study was not totally conclusive as both (P)RR downregulation and bafilomycin may only indirectly impair the response to (pro)renin by affecting other functions like intracellular trafficking.

Thus, thirteen years after the first description of (P)RR, its function as a receptor is still a matter of debate. The ability of (P)RR to interact with its putative ligands and elicit cellular responses has mainly been confirmed in vitro and in cell culture (5, 18-22) (for review see (23)). In vivo, its relevance lacks substantial evidence, like in the study of Kaneshiro et al., in which no direct role of (pro)renin can be ascertained concerning the increased ERK phosphorylation and cyclooxygenase-2 upregulation observed in the renal cortex of transgenic rats overexpressing the human (P)RR (24). In fact, experiments conducted in rodent models using a decoy peptide designed to block prorenin/(P)RR interaction, led to contradictory and inconsistent conclusions about the involvement of (P)RR in cardiovascular pathophysiology (19, 25-31) (for review see (23)), and the specificity and stability of the decoy peptide in vivo has yet to be proven (30, 32). More importantly, the link between (P)RR and (pro)renin is not supported by the comparison of the knockouts in the mouse. Complete (P)RR gene deletion leads to embryonic lethality (23), and the first tissue-specific knockouts reported to date die soon after birth due to massive tissue degeneration and defective cellular autophagy (see chapter 5). These phenotypes do not correlate with those of the knockouts of the various RAS components, which mainly display cardiovascular and metabolic syndromes (33-35).

Another important function described recently for (P)RR is its role in Wnt signaling. Cruciat et al. were the first to characterize it in Xenopus as a coreceptor in the canonical Wnt signaling pathway, interacting by its extracellular domain with the seven transmembrane receptor Frizzled 8 (Fz8) and the low-density lipoprotein receptor-related protein 6 (LRP6) (36). Later, the involvement of (P)RR in the non-canonical Wnt signaling pathway was also demonstrated in two studies studying the Planar Cell Polarity (PCP) process in Drosophila (37, 38). This role of (P)RR in both canonical and non-canonical Wnt pathways were reported to be independent of the RAS. Again in these studies, the subcellular localization of (P)RR in relation to its function is unclear. Buechling et al. were the only ones to assess this question by immunofluorescence and showed it mainly at the plasma membrane of Drosophila ovarian cells in culture, although not exclusively since a significant amount of the receptor was also located in a perinuclear compartment (37). Cruciat et al. (36) did not report on (P)RR subcellular distribution, but as the interaction of Wnt ligands with their receptors occur at the plasma membrane, one can hypothesize the same for (P)RR.

However, the molecular mechanisms proposed in these studies do not suggest that the function of (P)RR is restricted to the plasma membrane. Cruciat et al. showed that (P)RR (directly or indirectly) interacts with two subunits of the integral (membrane) domain of the V-ATPase, which suggests that (P)RR is also localized within the intracellular organelles in which the V-ATPase function takes place (36). The V-ATPase is a multi-subunit complex involved in organelle acidification, thereby promoting vesicle trafficking and notably endocytosis (39). A possibility would be that (P)RR actually shuttles between the plasma membrane and some intracellular vesicles such as the so-called signalosomes (40), and serves as an adaptor bridging canonical Wnt signaling to endocytosis for optimal activation. Similarly, both Buechling and Hermle reported that in (P)RR mutant flies, Fz is retained in intracellular vesicles, suggesting that (P)RR might be required for Fz targeting to the plasma membrane (37, 38). Thus, besides being plasma membrane-associated, Fz and (P)RR might be mutually required for plasma membrane targeting and subsequently efficient Wnt-PCP signaling. Thus, (P)RR might regulate protein trafficking e.g. from the post Golgi network to the plasma membrane, or recycling between the plasma membrane and the endosomal compartment.


Is an intracellular localization of (P)RR incompatible with a function as a receptor for (pro)renin? In view of the fact that (pro)renin needs to transit through intracellular vesicles before being exocytosed, it cannot be excluded that the two interact at that level in certain (renin-producting) cell types.

However, there is more evidence for an interaction of (P)RR with the V-ATPase, suggested as early as 1998 (6). Recent reports of the first tissue-specific deletions of (P)RR in the mouse, strengthen the hypothesis that the receptor may influence the V-ATPase function by shedding light on a potential role in autophagy. Autophagy is a general term for a process of self-degradation of cellular components, during which these components are engulfed into autophagosomes that ultimately fuse to lysosomes (41-44). Mice with a specific deletion of (P)RR in cardiomyocytes developed heart failure and died within 3 weeks of age (45). The cellular mechanism proposed was an impaired vesicular acidification leading to the accumulation of numerous autophagic vacuoles containing undigested cellular components. In addition, gene deletion in mouse embryonic fibroblasts in culture revealed a downregulation of V0 subunits of the V-ATPase, essential for autophagy due to its crucial role in the acidification of lysosomes and their fusion with autophagosomes (13, 39, 46). A similar impairment in autophagy has been observed in yeast after ablation of some assembly proteins and the loss of one V0 subunit (47, 48). Similar results were described for podocyte-specific (P)RR knockout mice, which developed congenital nephrotic syndrome and died within 3 to 4 weeks of age (49, 50). In addition to blocking autophagy, disruption of pH homeostasis altered cytoskeleton arrangement and podocyte morphology and led to necrosis. In view of the fact that the M8-9 fragment has been described as an accessory subunit Atp6ap2 of the V-ATPase (6), these three articles (45, 49, 50) were the first to suggest a molecular mechanism by which (P)RR can act on V-ATPase function, by controlling its assembly and stability. However, it is important to note that the molecular mechanism is not really proven yet. The disruption of the V-ATPase complex and the impairment in vesicle acidification and autophagy may not be the result of a direct effect of (P)RR on the V-ATPase but the indirect consequence of other cellular defects.


It is interesting that although various functions have been proposed for (P)RR such as being a receptor for (pro)renin, a co-receptor for Wnt signaling, or a subunit for the V-ATPase, all the phenotypes observed when (P)RR expression is impaired can be explained at least in part, by dysregulations of basic cellular functions such as intracellular trafficking. A better understanding of how this protein transits and distributes inside the cell may prove useful to confirm already described functions, or instead give hints for unraveling unexpected ones.


Gabin Sihn (g.sihn@mdc-berlin.de) and Celine Burckle (cburckle@necker.fr) equally contributed to this paper. The Deutsche Forschungsgemeinschaft (BA1374/20-1) and the Deutsche Akademische Austausch Dienst (Procope) supported this work. The authors are not aware of interest conflicts.


1. M. Bader: Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy. Annu Rev Pharmacol Toxicol, 50, 439-65 (2010)

2. G. Nguyen, F. Delarue, J. Berrou, E. Rondeau and J. D. Sraer: Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int, 50(6), 1897-903 (1996)

3. G. Nguyen, F. Delarue, C. Burckle, L. Bouzhir, T. Giller and J. D. Sraer: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest, 109(11), 1417-27 (2002)
PMid:12045255    PMCid:150992

4. G. Nguyen: Renin/prorenin receptors. Kidney Int, 69(9), 1503-6 (2006)

5. W. W. Batenburg, M. Krop, I. M. Garrelds, R. de Vries, R. J. de Bruin, C. A. Burckle, D. N. Muller, M. Bader, G. Nguyen and A. H. Danser: 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(12), 2441-53 (2007)

6. J. Ludwig, S. Kerscher, U. Brandt, K. Pfeiffer, F. Getlawi, D. K. Apps and H. Schagger: Identification and characterization of a novel 9.2-kDa membrane sector-associated protein of vacuolar proton-ATPase from chromaffin granules. J Biol Chem, 273(18), 10939-47 (1998)

7. A. Amsterdam, R. M. Nissen, Z. Sun, E. C. Swindell, S. Farrington and N. Hopkins: Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci U S A, 101(35), 12792-7 (2004)
PMid:15256591    PMCid:516474

8. R. J. Nuckels, A. Ng, T. Darland and J. M. Gross: The vacuolar-ATPase complex regulates retinoblast proliferation and survival, photoreceptor morphogenesis, and pigmentation in the zebrafish eye. Invest Ophthalmol Vis Sci, 50(2), 893-905 (2009)

9. C. Cousin, D. Bracquart, A. Contrepas, P. Corvol, L. Muller and G. Nguyen: Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension, 53(6), 1077-82 (2009)

10. A. Yoshikawa, Y. Aizaki, K. Kusano, F. Kishi, T. Susumu, S. Iida, S. Ishiura, S. Nishimura, M. Shichiri and T. Senbonmatsu: The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space. Hypertens Res, 34(5), 599-605 (2011)

11. A. Contrepas, J. Walker, A. Koulakoff, K. J. Franek, F. Qadri, C. Giaume, P. Corvol, C. E. Schwartz and G. Nguyen: A role of the (pro)renin receptor in neuronal cell differentiation. Am J Physiol Regul Integr Comp Physiol, 297(2), R250-7 (2009)
PMid:19474391    PMCid:2724237

12. A. Advani, D. J. Kelly, A. J. Cox, K. E. White, S. L. Advani, K. Thai, K. A. Connelly, D. Yuen, J. Trogadis, A. M. Herzenberg, M. A. Kuliszewski, H. Leong-Poi and R. E. Gilbert: The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H+-ATPase in the kidney. Hypertension, 54(2), 261-9 (2009)

13. S. Takamori, M. Holt, K. Stenius, E. A. Lemke, M. Gronborg, D. Riedel, H. Urlaub, S. Schenck, B. Brugger, P. Ringler, S. A. Muller, B. Rammner, F. Grater, J. S. Hub, B. L. De Groot, G. Mieskes, Y. Moriyama, J. Klingauf, H. Grubmuller, J. Heuser, F. Wieland and R. Jahn: Molecular anatomy of a trafficking organelle. Cell, 127(4), 831-46 (2006)

14. C. Burckle and M. Bader: Prorenin and its ancient receptor. Hypertension, 48(4), 549-51 (2006)

15. J. S. Bonifacino and L. M. Traub: Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem, 72, 395-447 (2003)

16. J. H. Schefe, M. Menk, J. Reinemund, K. Effertz, R. M. Hobbs, P. P. Pandolfi, P. Ruiz, T. Unger and H. Funke-Kaiser: 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(12), 1355-66 (2006)

17. T. Kato, D. Du, F. Suzuki and E. Y. Park: Localization of human (pro)renin receptor lacking the transmembrane domain on budded baculovirus of Autographa californica multiple nucleopolyhedrovirus. Appl Microbiol Biotechnol, 82(3), 431-7 (2009)

18. D. Du, T. Kato, F. Suzuki and E. Y. Park: Expression of protein complex comprising the human prorenin and (pro)renin receptor in silkworm larvae using Bombyx mori nucleopolyhedrovirus (BmNPV) bacmids for improving biological function. Mol Biotechnol, 43(2), 154-61 (2009)

19. S. Feldt, W. W. Batenburg, I. Mazak, U. Maschke, M. Wellner, H. Kvakan, R. Dechend, A. Fiebeler, C. Burckle, A. Contrepas, A. H. Jan Danser, M. Bader, G. Nguyen, F. C. Luft and D. N. Muller: 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(3), 682-8 (2008)

20. Y. Huang, S. Wongamorntham, J. Kasting, D. McQuillan, R. T. Owens, L. Yu, N. A. Noble and W. Border: Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int, 69(1), 105-13 (2006)

21. J. J. Saris, P. A. t Hoen, I. M. Garrelds, D. H. Dekkers, J. T. den Dunnen, J. M. Lamers and A. H. Jan Danser: Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. Hypertension, 48(4), 564-71 (2006)

22. A. Zhou, R. W. Carrell, M. P. Murphy, Z. Wei, Y. Yan, P. L. Stanley, P. E. Stein, F. Broughton Pipkin and R. J. Read: A redox switch in angiotensinogen modulates angiotensin release. Nature, 468(7320), 108-11 (2010)
PMid:20927107    PMCid:3024006

23. G. Sihn, A. Rousselle, L. Vilianovitch, C. Burckle and M. Bader: Physiology of the (pro)renin receptor: Wnt of change? Kidney Int, 78(3), 246-56 (2010)

24. Y. Kaneshiro, A. Ichihara, T. Takemitsu, M. Sakoda, F. Suzuki, T. Nakagawa, M. Hayashi and T. Inagami: Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats. Kidney Int, 70(4), 641-6 (2006)

25. A. Ichihara, M. Hayashi, Y. Kaneshiro, F. Suzuki, T. Nakagawa, Y. Tada, Y. Koura, A. Nishiyama, H. Okada, M. N. Uddin, A. H. Nabi, Y. Ishida, T. Inagami and T. Saruta: Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J Clin Invest, 114(8), 1128-35 (2004)
PMid:15489960    PMCid:522242

26. A. Ichihara, Y. Kaneshiro, T. Takemitsu, M. Sakoda, F. Suzuki, T. Nakagawa, A. Nishiyama, T. Inagami and M. Hayashi: Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension, 47(5), 894-900 (2006)

27. A. Ichihara, F. Suzuki, T. Nakagawa, Y. Kaneshiro, T. Takemitsu, M. Sakoda, A. H. Nabi, A. Nishiyama, T. Sugaya, M. Hayashi and T. Inagami: Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol, 17(7), 1950-61 (2006)

28. Y. Kaneshiro, A. Ichihara, M. Sakoda, T. Takemitsu, A. H. Nabi, M. N. Uddin, T. Nakagawa, A. Nishiyama, F. Suzuki, T. Inagami and H. Itoh: Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. J Am Soc Nephrol, 18(6), 1789-95 (2007)

29. D. N. Muller, B. Klanke, S. Feldt, N. Cordasic, A. Hartner, R. E. Schmieder, F. C. Luft and K. F. Hilgers: (Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. Hypertension, 51(3), 676-81 (2008)

30. J. L. Wilkinson-Berka, R. Heine, G. Tan, M. E. Cooper, K. M. Hatzopoulos, E. L. Fletcher, K. J. Binger, D. J. Campbell and A. G. Miller: RILLKKMPSV influences the vasculature, neurons and glia, and (pro)renin receptor expression in the retina. Hypertension, 55(6), 1454-60 (2010)

31. J. Huang, L. C. Matavelli and H. M. Siragy: Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-beta1-connective tissue growth factor signalling cascade. Clin Exp Pharmacol Physiol, 38(4), 215-21 (2011)
PMid:21265872    PMCid:3077929

32. S. Feldt, U. Maschke, R. Dechend, F. C. Luft and D. N. Muller: The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling. J Am Soc Nephrol, 19(4), 743-8 (2008)
PMid:18235083    PMCid:2390971

33. M. Bader: Mouse knockout models of hypertension. Methods Mol Med, 108, 17-32 (2005)

34. M. Bader, H. Bohnemeier, F. S. Zollmann, O. E. Lockley-Jones and D. Ganten: Transgenic animals in cardiovascular disease research. Exp Physiol, 85(6), 713-31 (2000)

35. K. Yanai, T. Saito, Y. Kakinuma, Y. Kon, K. Hirota, K. Taniguchi-Yanai, N. Nishijo, Y. Shigematsu, H. Horiguchi, Y. Kasuya, F. Sugiyama, K. Yagami, K. Murakami and A. Fukamizu: Renin-dependent cardiovascular functions and renin-independent blood-brain barrier functions revealed by renin-deficient mice. J Biol Chem, 275(1), 5-8 (2000)

36. C. M. Cruciat, B. Ohkawara, S. P. Acebron, E. Karaulanov, C. Reinhard, D. Ingelfinger, M. Boutros and C. Niehrs: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science, 327(5964), 459-63 (2010)

37. T. Buechling, K. Bartscherer, B. Ohkawara, V. Chaudhary, K. Spirohn, C. Niehrs and M. Boutros: Wnt/Frizzled signaling requires dPRR, the Drosophila homolog of the prorenin receptor. Curr Biol, 20(14), 1263-8 (2010)

38. T. Hermle, D. Saltukoglu, J. Grunewald, G. Walz and M. Simons: Regulation of Frizzled-dependent planar polarity signaling by a V-ATPase subunit. Curr Biol, 20(14), 1269-76 (2010)

39. V. Marshansky and M. Futai: The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Curr Opin Cell Biol, 20(4), 415-26 (2008)

40. R. Dobrowolski and E. M. De Robertis: Endocytic control of growth factor signalling: multivesicular bodies as signalling organelles. Nat Rev Mol Cell Biol, 13(1), 53-60 (2011)
PMid:22108513    PMCid:3374592

41. B. Levine, N. Mizushima and H. W. Virgin: Autophagy in immunity and inflammation. Nature, 469(7330), 323-35 (2011)
PMid:21248839    PMCid:3131688

42. N. Mizushima: Autophagy: process and function. Genes Dev, 21(22), 2861-73 (2007)

43. N. Mizushima and B. Levine: Autophagy in mammalian development and differentiation. Nat Cell Biol, 12(9), 823-30 (2010)
PMid:20811354    PMCid:3127249

44. D. C. Rubinsztein, G. Marino and G. Kroemer: Autophagy and aging. Cell, 146(5), 682-95 (2011)

45. K. Kinouchi, A. Ichihara, M. Sano, G. H. Sun-Wada, Y. Wada, A. Kurauchi-Mito, K. Bokuda, T. Narita, Y. Oshima, M. Sakoda, Y. Tamai, H. Sato, K. Fukuda and H. Itoh: The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes. Circ Res, 107(1), 30-4 (2010)

46. M. Forgac: Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol, 8(11), 917-29 (2007)

47. L. A. Graham, B. Powell and T. H. Stevens: Composition and assembly of the yeast vacuolar H(+)-ATPase complex. J Exp Biol, 203(Pt 1), 61-70 (2000)

48. R. Hirata, N. Umemoto, M. N. Ho, Y. Ohya, T. H. Stevens and Y. Anraku: VMA12 is essential for assembly of the vacuolar H(+)-ATPase subunits onto the vacuolar membrane in Saccharomyces cerevisiae. J Biol Chem, 268(2), 961-7 (1993)

49. Y. Oshima, K. Kinouchi, A. Ichihara, M. Sakoda, A. Kurauchi-Mito, K. Bokuda, T. Narita, H. Kurosawa, G. H. Sun-Wada, Y. Wada, T. Yamada, M. Takemoto, M. A. Saleem, S. E. Quaggin and H. Itoh: Prorenin receptor is essential for normal podocyte structure and function. J Am Soc Nephrol, 22(12), 2203-12 (2011)

50. F. Riediger, I. Quack, F. Qadri, B. Hartleben, J. K. Park, S. A. Potthoff, D. Sohn, G. Sihn, A. Rousselle, V. Fokuhl, U. Maschke, B. Purfurst, W. Schneider, L. C. Rump, F. C. Luft, R. Dechend, M. Bader, T. B. Huber, G. Nguyen and D. N. Muller: Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol, 22(12), 2193-202 (2011)

Key Words: (Pro)renin receptor, Renin-Angiotensin System, Vacuolar H+- ATPase, Wnt signaling, Autophagy

Send correspondence to: Michael Bader, Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin-Buch, Germany, Tel: 49 30 9406 2193, Fax: 49 30 9406 2110, E-mail:mbader@mdc-berlin.de