REVIEW(Pro)renin Receptor and Vacuolar H+−ATPase
Atsuhiro Ichihara

Department of Medicine II, Endocrinology and Hypertension,
Tokyo Women’s Medical University, Tokyo, Japan(Received for publication on August 9, 2011)(Revised for publication on September 14, 2011)(Accepted for publication on November 17, 2011)

The (pro)renin receptor [(P)RR] is a molecule that binds prorenin and renin in tissues, leading not only
to their activation, but also carrying out intracellular signaling. As a key player in the tissue renin–angiotensin system, (P)RR activation plays an important role in the development of end-organ damage inhypertension and diabetes. One fragment of (P)RR is also known as ATP6AP2 because it is associatedwith vacuolar H+-ATPase (V-ATPase). V-ATPase is a multi-subunit proton pump involved in diverseand fundamental aspects of cellular physiology, including receptor-mediated endocytosis and recycling,processing of proteins and signaling molecules, membrane sorting and trafficking, and activation oflysosomal/autophagosomal enzymes. The role of (P)RR in the function of V-ATPase has been investigated in recent studies using conditional knockout mice. Furthermore, the novel function of (P)RR as
an adaptor protein between the Wnt receptor complex and V-ATPase has been demonstrated. Thus, (P)RR is a multi-functional molecule that has complex structure and functionality. This review focuses oncurrent insights into the possibility of (P)RR acting as a modulator of V-ATPase and future perspectives
in translational research. (Keio J Med 61 (3) : 73–78, September 2012)

Keywords: renin–angiotensin system, signal transduction, V-ATPase, vesicular acidification

tein between the Wnt receptor complex and V-ATPase.7
Thus, (P)RR is a multi-functional molecule that exhibits
complex structure and functionality. This review highlights the physiological effects of (P)RR on the functionof mammalian V-ATPase.

Introduction
The (pro)renin receptor [(P)RR] was first identified asa receptor for renin and prorenin in 2002.1 Binding with(P)RR not only induces the enzymatic activation of renin
and prorenin but also induces angiotensin II-independent
intracellular signaling. (P)RR has been shown to play a
key role in the tissue renin–angiotensin system (RAS),
and the actions induced by its own intracellular signaling
play an important role in the development of end-organ
damage in hypertension and diabetes.2–5 Recent studies
revealed that (P)RR is an integral component of mammalian vacuolar-type H+-ATPase (V-ATPase), which
is a multi-subunit proton pump involved in diverse andfundamental aspects of cellular physiology, including receptor-mediated endocytosis and recycling, processing ofproteins and signaling molecules, membrane sorting andtrafficking, and activation of lysosomal/autophagosomal
enzymes.6 In addition, (P)RR works as an adaptor pro-

Roles of (P)RR in Pathophysiology
Prorenin is an inactive proenzyme for active renin.
Nevertheless, plasma prorenin levels are elevated in patients with diabetes mellitus compared with healthy subjects, and this elevation predicts microvascular complications in diabetic patients.8–10 The cause of this increase inprorenin levels is unclear, but may reflect increased prorenin gene expression and/or decreased prorenin clearance. The prorenin molecule contains a region called theprorenin prosegment, which consists of a 43-amino-acidsequence at the N-terminus of the renin molecule. The
prorenin prosegment is thought to cover the enzyme ac-

Reprint requests to: Atsuhiro Ichihara, MD, PhD, FAHA, Professor and Chairman, Department of Medicine II, Institute of Endocrinology andHypertension, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan, E-mail: atzichi@endm.twmu.ac.jp
Copyright © 2012 by The Keio Journal of Medicine73

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Ichihara A: (P)RR and V-ATPasetive site (the “closed” formation) and prevents access ofangiotensinogen to the site. Prorenin can be activatedproteolytically or nonproteolytically. The main physiological pathway for the activation of renin is proteolytic
cleavage of the prorenin prosegment, which opens up theactive site for angiotensinogen and its subsequent cleavage to angiotensin I. In vivo, proteolytic activation ofprorenin occurs almost exclusively in the juxtaglomerular cells within the kidney. Nonproteolytic activation ofprorenin is a reversible process and can be viewed as theprorenin prosegment unfolding from the enzymatic cleft.
Nonproteolytic activation can be induced in vitro by low
temperatures or low pH (optimal at pH 3.3).11 (P)RR was
found to induce nonproteolytic activation of prorenin.1(P)RR-bound prorenin becomes enzymatically active asa result of a conformational change without cleavage ofthe prosegment, and thereby becomes able to produce local angiotensin I, which subsequently generates angiotensin II. Therefore, (P)RR provides reasonable explanations of the significance and enzymatic role of prorenin in
end-organ damage in diseases associated with the tissue
activation of RAS, such as hypertension, diabetes, andpreeclampsia.2–5,12 Moreover, (P)RR possesses its own intracellular signaling capability. Activated (P)RR induces
the mitogen activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) 1/2 and p38 pathways,
leading to upregulation of profibrotic and cyclooxygenase-2 genes independent of angiotensin II generation;
this upregulation contributes to the pathophysiology of
end-organ damage. (P)RR blockade has been shown toattenuate end-organ damage in hypertensive and diabetic
models.2–5
Roles of (P)RR in Development
Previous reports have suggested a possible relationshipof (P)RR with V-ATPase. Mouse embryonic stem cells
deficient in (P)RR failed to generate chimeras when injected into blastocysts, in contrast to the successful birthof renin, angiotensinogen, and angiotensin type 1 receptor
knockout mice.13–15 Zebrafish with mutant (P)RR display
early developmental abnormalities, including eye andbody hypopigmentation, as well as neuronal cell death,and die early in development, implicating the critical
function of (P)RR in melanocytes and neurons.16 Zebrafish embryos with mutant V-ATPase subunits and thosewith mutant (P)RR share similar phenotypes,16 indicating
a possible link between these two proteins. Similar phenotypes such as small heads, shortened tails, and defects
in melanocyte and eye pigmentation were also observedin Xenopus when morpholino antisense RNA against (P)RR was injected into embryos.7 An exonic splice enhancer mutation of human (P)RR is associated with a familywith X-linked mental retardation and epilepsy, allowing
us to speculate that (P)RR may play an important role inthe synaptic vesicles.17,18 These phenotypes related to themutation or deletion of (P)RR suggest essential roles for(P)RR in development.
(P)RR-deleted embryonic stem cells do not form chimeras after blastocyst injection.19 To circumvent thisembryonic lethality, the tissue-specific (P)RR knockout
mouse was created.6 Based on the roles of (P)RR underpathological conditions, the genetic ablation of (P)RR
had been expected to be protective. However, cardiomyocyte-specific (P)RR knockout mice developed fulminantheart failure and inevitably died young. (P)RR-depleted
cardiomyocytes displayed the perinuclear accumulationof numerous vacuoles, including multi-vesicular bodies
and autophagolysosomes, which appeared to be caused
by RAS-independent mechanisms. A C-terminal fragment of (P)RR was identified as vacuolar adenosine triphosphatase (V-ATPase), H+-transporting, lysosomal
accessory protein 2 (ATP6AP2),20 which plays an essential role in controlling the intracellular vesicular acidenvironment.21 Investigation of the underlying cellularmechanisms accounting for the incredible phenotypes
observed in (P)RR-ablated cardiomyocytes identified
a role for (P)RR in the function of V-ATPase, and disclosed that (P)RR is an accessory subunit to mammalian
V-ATPase, important, in particular, for the stability andassembly of V0 subunits.
V-ATPase-related Physiological Function of (P)RR
V-ATPase is a large multi-subunit, membrane-associated protein complex that carries out active transport ofprotons across the membrane, thereby affecting the acidic
environment of intracellular compartments and of the extracellular space (Fig. 1). V-ATPase is expressed in mostkinds of cells and is widely distributed in various subcellular compartments such as the trans-Golgi network, endosomes, lysosomes, secretory granules, melanosomes,
synaptic vesicles, and endocytic vesicles. As shown in
Table 1, V-ATPase-dependent acidification of organelles
facilitates protein sorting, membrane trafficking and fusion, receptor-mediated endocytosis and recycling, andlysosomal/autophagosomal protein degradation.22 For
instance, hydrolases responsible for protein degradationin the lysosome have optimal activity at a low pH. pH isalso involved in diverse cellular processes such as phagocytosis, virus entry, metastasis, and embryonic left–rightpatterning.22,23 In intracellular vesicles, V-ATPase also
serves as a pH sensor to regulate trafficking.24 (P)RR
might also sense the acidity levels of intracellular compartments and regulate V-ATPase activity accordingly.6
Mutations in V-ATPase components, including (P)RR,
or pharmacological inhibition of V-ATPase activity leads
to the disruption of pH homeostasis. This results in an
accumulation of membrane proteins in endocytic compartments and in some cases blocks transport between
the late endosome and the lysosome, leading to lethality
in various organisms.6,25 In addition, specific V-ATPaseKeio J Med 2012; 61 (3): 73–78

75

Fig. 1 Putative structure of mammalian vacuolar-type H+-ATPase and the (pro)renin receptor.
A, B, C, D, E, F, G, H, a, c, c′′, d, e, AC45: subunits of vacuolar-type H+-ATPase.
Reproduced with permission from Lippincott Williams & Wilkins.6

complexes participate in highly differentiated cellular
and tissue functions, including urine acidification in renal intercalated cells and bone resorption in osteoclasts.
V-ATPase complexes are also abundant in endocrine tissues, such as β cells in the pancreas and chromaffin cells
in adrenal glands, participating in exocytosis in the regulated hormone secretion in an acidification-independent

manner.26,27 This ubiquitous and specific distribution of
V-ATPase suggests that the enzyme is required for diverse fundamental roles in cellular physiology, and underscores the significance for the cell survival. Since theaccumulation of intracellular vesicles in (P)RR-ablated
cardiomyocytes was reproduced by the V-ATPase pharmacological inhibitor bafilomycin, it is clear that several

Table 1 Vacuolar H+-ATPase (V-ATPase)-dependent cellular mechanisms and their contributing physiological functions in mammals
V-ATPase in organelles
Protein sorting
Membrane trafficking and fusion
Receptor-mediated endocytosis and recycling
Lysosomal/autophagosomal degradation
V-ATPase in plasma membranes
Acid secretion
Cell-to-cell fusion

Examples of physiological functions
Conversion of proinsulin to insulin in β cells
Hormone secretion from endocrine cells
Receptor expression at plasma membranes
Cellular recycling system
Urine acidification in renal intercalated cells
Bone resorption in osteoclasts
Metastasis of malignancy
Infection by HIV and influenzae

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Ichihara A: (P)RR and V-ATPase

Fig. 2 The structure of the (pro)renin receptor.
SP, signal peptide; ECD, extracellular domain; TM, transmembrane domain; CD, cytosolic domain.
Reproduced with permission from Frontiers in Bioscience (http://www.bioscience.org).41

physiological roles of (P)RR can be attributed to the functions of V-ATPase.
Structure, Cellular Localization, and Function of (P)RR
In humans, the (P)RR gene is located on the X chromosome at locus p11.4. (P)RR messenger RNA is 2034
base pairs long and there is no alternative splicing product. The protein is composed of 350 amino acids and has
a predicted mass of 37 kDa. (P)RR contains four different domains: an N-terminal signal peptide, an extracellular domain, a single transmembrane domain, and ashort cytosolic domain (Fig. 2).28 The extracellular domain is responsible for binding with renin and prorenin,
whereas the transmembrane and cytosolic domains areassociated with V-ATPase. Unlike other components of
RAS, the (P)RR gene is highly conserved among species,and (P)RR orthologs are found in many species, including rat, mouse, chicken, as well as in more primitive species such as frog, zebrafish, Caenorhabditis elegans, andDrosophila melanogaster,19 in which the role of RAS is
unlikely to be meaningful. The degree of homology of(P)RR between human, rat, and mouse is about 95% for
the nucleotide sequence and over 80% at the amino-acidlevel.29 Thus (P)RR is an evolutionally conserved protein
despite having no yeast orthologs. The highest level ofhomology is found in the transmembrane and cytoplasmic regions corresponding to ATP6AP2, discovered inbovine chromaffin granules.20 This corroborates the mostfundamental function of (P)RR – working as a subunit of
V-ATPase. In addition, the extracellular domain displays
high amino acid sequence identity exclusively in vertebrates.19 Because RAS emerged relatively late in evolution, the ATP6AP2 protein may have acquired renin- andprorenin-binding properties.30 Consequently, RAS could
affect the intracellular vesicular environment by modulating V-ATPase function via (P)RR.
(P)RR was thought to be localized mainly on the plasma
membrane. However, recent studies revealed that most(P)RR is found in the intracellular regions, particularlyaround the nucleus, which is in line with the subcellular
localization of V-ATPase.31,32 In fact, sequence analysis
disclosed that the cytosolic domain of (P)RR carries anendosomal/lysosomal sorting signal as well as endoplasmic reticulum retention motifs.19 Previous studies havealso demonstrated that (P)RR is found in the trans-Golgi
network, where it undergoes cleavage by proteases suchas proprotein convertase furin and ADAM19 to generate a 28-kD N-terminal soluble fragment that is secreted
outside the cell, along with a 10-kD C-terminal residue
that likely represents ATP6AP2.33 Consistent with this,the N-terminal fragment of (P)RR is present in plasma
and urine.33 However, there are still many issues to be resolved: whether V-ATPase requires full-length (P)RR or
still functions with truncated (P)RR, whether (P)RR always accompanies V-ATPase or sometimes exists alone,
whether the amount of soluble (P)RR reflects the state of
the intracellular environment, and to what extent soluble(P)RR contributes to the local RAS. The function of (P)Keio J Med 2012; 61 (3): 73–78

RR could be determined by its cellular localization andits form. Future study must address these issues and unravel the complex behavior of this molecule.
Wnt Signals and (P)RR at Plasma Membranes
Recently, the novel function of (P)RR as an adaptor protein between the Wnt receptor complex and VATPase was discovered in Drosophila and Xenopus using genomewide siRNA screening.7,34,35 Wnt signaling
is involved in virtually every aspect of embryonic development and also controls homeostatic self-renewal ina number of adult tissues; it is also implicated in tumor
formation.36 Wnts bind to the seven-pass transmembrane
receptor Frizzled, which enables Frizzled to cooperate with single-pass transmembrane proteins LRP5 and
LRP6. Currently, Wnt receptor activation is believed toactivate three different pathways: the canonical Wnt/βcatenin cascade, the noncanonical planar cell polarity(PCP) pathway, and the Wnt/Ca2+ pathway.36 Since Wnt
signaling was disturbed by the inhibition of V-ATPase
function through the knock down of either (P)RR or other
V-ATPase subunits and by pharmacological inhibitors of
V-ATPase, (P)RR seems to mediate the internalization of
the receptors and the subsequent proper signal transduction as a hinge molecule between the Wnt receptor and VATPase. Furthermore, it has been shown that V-ATPaseis also required for the activation of the Notch receptor
in physiological and pathological settings.37,38 Therefore,
the acidification of an intracellular compartment could bea crucial factor for a wide variety of signal transductions.
Indeed, this appears to be applicable also to (P)RR-mediated signaling itself. The inhibition of V-ATPase withbafilomycin attenuates ERK 1/2 phosphorylation induced
by renin and prorenin in collecting duct/distal tubule lineage Madin-Darby canine kidney cells.31 However, the attenuation of ERK 1/2 phosphorylation could be explainedby the effects of other intracellular signal transductions
rather than by the direct influence of (P)RR-mediatedsignaling. V-ATPase-mediated vesicular acidification isnecessary for proper signal transduction by controlling
receptor-mediated endocytosis and receptor recycling.
Therefore, bafilomycin might have disturbed granularacidification, thereby nonspecifically suppressing various
signal transductions. Future studies should address theimportant issue of whether ERK 1/2 phosphorylation is
attributed to (P)RR-specific intracellular signaling or toligand nonspecific signaling.
Future Perspectives(P)RR is an accessory subunit of mammalian V-ATPaseas well as the receptor for renin and prorenin. Although
there is currently no explanation as to why a subunit of
V-ATPase acquired the function of a receptor for renin
and prorenin, tissue RAS and the intracellular environ-77

ment may be interconnected and mutually regulated via(P)RR. In fact, (P)RR blockade appeared to have benefits
in animal models of diabetes and hypertension by inhibiting the tissue renin–angiotensin system;2–5 however,
several studies have reported conflicting results.39,40 (P)RR blockade might also have adverse effects because it
affects the activity of V-ATPase. If we can discover exactly to what extent the extracellular domain of (P)RR
contributes to the function of V-ATPase, then translational research regarding (P)RR might provide a new strategy
for treatment of chronic kidney diseases, osteomalacia,
malignancy, infection, and endocrine disorders in addition to hypertension and diabetes.
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