Clinical Science (2011) 120, 169–178 (Printed in Great Britain) doi:10.1042/CS20100432
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Renin, (pro)renin and receptor: an update
Genevieve NGUYEN
Institut National de la Santé et de la Recherche Médicale (INSERM) and Collège de France ‘Early Development and
Pathologies’ Center for Interdisciplinary Research in Biology and Experimental Medicine Unit, 11 place Marcelin Berthelot,
75005, Paris, France
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PRR [(pro)renin receptor] was named after its biological characteristics, namely the binding of
renin and of its inactive precursor prorenin, that triggers intracellular signalling involving ERK
(extracellular-signal-regulated kinase) 1/2. However the gene encoding for PRR is named ATP6ap2
(ATPase 6 accessory protein 2) because PRR was initially found as a truncated form co-purifying
with V-ATPase (vacuolar H+ -ATPase). There are now data showing that this interaction is not only
physical, but also functional in the kidney and the heart. However, the newest and most fascinating
development of PRR is its involvement in both the canonical Wnt/β-catenin and non-canonical
Wnt/PCP (planar cell polarity) pathways, which are essential for adult and embryonic stem cell
biology, embryonic development and disease, including cancer. In the Wnt/β-catenin pathway, it
has been shown that PRR acts as an adaptor between the Wnt receptor LRP5/6 (low-density
lipoprotein receptor-related protein 5/6) and Fz (frizzled) and that the proton gradient generated
by the V-ATPase in endosomes is necessary for LRP5/6 phosphorylation and β-catenin activation.
In the Wnt/PCP pathway, PRR binds to Fz and controls its asymetrical subcellular distribution and
therefore the polarization of the cells in a plane of a tissue. These essential cellular functions of
PRR are independent of renin and open new avenues on the pathophysiological role of PRR. The
present review will summarize our knowledge of (pro)renin-dependent functions of PRR and will
discuss the newly recognized functions of PRR related to the V-ATPase and to Wnt signalling.
INTRODUCTION
A receptor for renin and for the inactive proenzyme form
of renin prorenin was cloned in 2002 and was called
PRR [(pro)renin receptor] [1]. Rapidly, it became clear
that PRR was the full-length form of a smaller protein
described previously associated with the V-ATPase
(vacuolar H+ -ATPase) [2,3] and this is why the PRR
gene is named ATP6AP2 (ATPase 6 accessory protein
2)/PRR. In humans, there is a unique ATP6AP2/PRR
gene on the X chromosome encoding a unique protein
that undergoes intracellular processing, such that PRR
exists in three different molecular forms: (i) a fulllength integral TM (transmembrane) protein, (ii) a soluble
PRR (sPRR) found in plasma and urine, and (iii) a
truncated form composed of the transmembrane and
cytoplasmic domains [4,5]. Because PRR was identified as
a component of the RAS (renin–angiotensin system) and
Key words: cardiovascular disease, (pro)renin receptor (PRP), renal pathology, Wnt/β-catenin signalling, Wnt/planar cell polarity
signalling.
Abbreviations: ACE, angiotensin-converting enzyme; AngII, angiotensin II; AT1 R, AngII type 1 receptor; ATP6ap2, ATPase
6 accessory protein 2; BP, blood pressure; CNS, central nervous system; COX2, cyclo-oxygenase 2; EC, extracellular; ERK,
extracellular-signal-regulated kinase; Fz, frizzled; HRP, ‘handle region peptide’; IC, intracellular; LRP, low-density lipoprotein
receptor-related protein; MAPK, mitogen-activated protein kinase; α-MHC, α-myosin heavy chain; NGF, nerve growth factor;
PCP, planar cell polarity; PLZF, promyelocytic zinc finger transcription factor; PRR, (pro)renin receptor; SHR, spontaneously
hypertensive rat; SON, supraoptic nucleus; sPRR, soluble PRR; TGF-β, transforming growth factor-β; RAS, renin–angiotensin
system; TM, transmembrane; TNF-α, tumour necrosis factor-α; V-ATPase, vacuolar H+ -ATPase.
Correspondence: Dr Genevieve Nguyen (email [email protected]).
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because of its potential pro-fibrotic effects, it has been
primarily studied in cardiovascular and renal diseases.
Study of its pathophysiological role has been hampered
by the fact that total ablation of PRR was impossible,
suggesting an essential role in cell biology, and recent
data showing an unexpected involvement of PRR in VATPase function and in Wnt signalling pathways have
indeed corroborated this hypothesis (discussed below).
The present review will begin with a section on the
characteristics of PRR and the experimental data in favour
of a role of PRR in relation with (pro)renin in cardiovascular and renal diseases, followed by recent advances
in my laboratory on the structure of PRR, and a final
section describing the newly discovered functions of PRR
related to V-ATPase and to Wnt signalling, which are
totally independent of renin and prorenin.
PRR, (PRO)RENIN-DEPENDENT FUNCTIONS,
AND CARDIOVASCULAR AND RENAL
DISEASES
PRR binds renin and prorenin [collectively named
(pro)renin] with an affinity in the nanomolar range [1,6–
10], and their binding triggers a range of cellular events
depending on the cell type. Commonly, PRR activation
triggers the phosphorylation of the MAPKs (mitogenactivated protein kinases) ERK (extracellular-signalregulated kinase) 1/2, inducing the up-regulation of the
pro-fibrotic genes such as TGF-β1 (transforming growth
factor-β1), PAI-1 (plasminogen activator inhibitor-1),
collagens and fibronectin [1,7,8,11,12]. In addition, PRR
also up-regulates COX2 (cyclo-oxygenase 2) [13] and
activates the p38 MAPK/Hsp27 (heat-shock protein
27) pathway [14], PI3K (phosphoinositide 3-kinase)
p85 and PLZF (promyelocytic zinc finger transcription
factor) that represses the expression of PRR itself
[15,16]. Moreover, PRR-bound prorenin undergoes a
conformational change that opens its pro-segment and
uncovers the active site, so that, on a cell surface, prorenin
becomes enzymatically active [1,10,17,18]. Because PRR
was characterized as a new component of the RAS,
the first studies aimed to address its pathophysiological
role in hypertension and organ damage in situations
known to be associated with RAS activation. In order
to do so, as with other components of the RAS, several
groups tried to generate PRR − / − mice, which represents
the most powerful tool to study the role of a new
receptor. Against all odds, PRR-knockout mice could
not be generated and therefore research groups have
turned to transgenic animals overexpressing PRR or
have tried to design PRR antagonists. To date, evidence
that PRR is linked to cardiovascular and renal diseases
relies exclusively on studies in animals overexpressing
PRR and on the use of a putative PRR blocker. Indeed,
ubiquitous overexpression of human PRR in rats was
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associated with proteinuria, nephropathy and COX2
up-regulation in spite of normal renal levels of AngII
(angiotensin II) and BP (blood pressure) [13,19], whereas
overexpression of the human PRR gene in VSMCs
(vascular smooth-muscle cells) induced high BP and
increased heart rate but resulted in normal kidney
function [20], showing that increased PRR synthesis
could be linked in some way to altered cardiovascular and
renal functions. In an attempt to identify a compound able
to block renin and/or prorenin binding to PRR, Suzuki
et al. [21] observed that an antibody against a sequence
of the pro-segment of human prorenin (I11 PFLKRP15 )
was able to open the pro-fragment, yielding a ‘nonproteolytically’ activated prorenin, in a manner similar
to PRR-binding-induced prorenin activation. They also
tested the ability of a peptide mimicking this part of the
pro-segment called the HRP (‘handle region peptide’)
to block (pro)renin binding to PRR. HRP was infused
in several experimental models and, in particular, in
diabetic rodents that have increased renin and prorenin
synthesis. HRP was shown to be able to prevent or
even reverse diabetic nephropathy [22–25], and to block
ocular inflammation in endotoxin-induced uveitis [26],
ischaemia-induced retinal neovascularization [27] and
diabetic retinopathy [28–30]. Moreover, HRP could
decrease cardiac and renal fibrosis in stroke-prone SHRs
(spontaneously hypertensive rats) [31–33] and reduce
insulin resistance [34]. The great interest in PRR in
diabetic nephropathy and retinopathy is explained by the
fact that diabetic patients have low active renin levels,
but very high prorenin levels, which are reported to
be associated with and even to be predictive of the
occurrence of microvascular complications as evidenced
in microalbuminuria and retinopathy [35–38], but, in
spite of the low renin levels, RAS blockers have a tissueprotective effect, suggesting local RAS activation. In
addition, it has been shown that prorenin synthesis was
locally enhanced in the collecting duct of diabetic rats
[39], and many studies have also shown an up-regulation
of PRR in the kidney of diabetic humans [40] and rats
[41,42], so that the combination of increased prorenin
and PRR may create a local environment favourable for
PRR activation and for AngII generation. The increased
PRR synthesis was attributed to the activation of AT1 R
(AngII type 1 receptor) and NADPH oxidase activity,
but also to high glucose by a mechanism involving NF-κB
(nuclear factor κB) and AP1 (activator protein 1) [41,43].
In return, PRR activation enhances renal synthesis of the
inflammatory molecules TNF-α (tumour necrosis factorα) and IL-1β (interleukin-1β), maintaining the vicious
pro-inflammatory pro-fibrotic circle. Taken together,
the hypothesis that the non-proteolytic activation of
prorenin by PRR could be responsible for increased RAS
activation in diabetes was tempting and blocking prorenin
binding to PRR and prorenin enzymatic activation with
HRP, claiming it to be a PRR blocker, was a logical move.
Renin, (pro)renin and receptor: an update
However, if the first results with HRP created a lot of
excitation because they identified PRR as a new valuable
therapeutical target in organ damage, alas HRP did not
meet all of the expectations as a PRR blocker as it has
since failed to show any effects in many other studies or
even had adverse effects [30]. Furthermore, its ability to
inhibit (pro)renin binding to PRR was even questioned
in vitro, and the fact that HRP cannot block prorenin
binding and ERK activation by native PRR expressed on
the surface of a cell [10,12,44,45] must definitely rule out
its name of ‘PRR blocker’.
If the non-proteolytic activation of prorenin by
PRR is important in diabetes, then increased prorenin
levels in pregnancy [46] or in patients treated with
an ACE (angiotensin-converting enzyme) inhibitor [47]
should also be a real concern. To study whether
increased prorenin could be responsible for fibrosis,
two independent groups have generated transgenic
rats [48] and mice [49] respectively with inducible or
constitutive overexpression of prorenin. Their results
clearly show that increased prorenin up to 200 times the
normal concentrations and over a period of 6 months
is not associated with any cardiac or kidney fibrosis,
as assessed by histological examination and by PCR
analysis for TGF-β and collagens. Yet, the animals
had a severe hypertension attributed to the increased
generation of AngII, since it was controlled by ACE
treatment and because mice overexpressing active-sitemutated prorenin had BPs comparable with controls
[48,49].
In summary, on the basis of the absence of an
established PRR antagonist, the weak phenotype of
animals overexpressing PRR and the absence of fibrosis
in prorenin-overexpressing animals, we must admit that
the evidence for a role of PRR in cardiovascular and renal
diseases is not very strong at the moment and we are still
waiting for tissue-specific knockout mice to establish the
real pathophysiological role of PRR.
Apart from these experimental models focusing
on cardiovascular and renal diseases, data have been
published suggesting a role for PRR in the central control
of BP. Indeed, we have shown that PRR is expressed in
nuclei important in the central control of BP, including
the SON (supraoptic nucleus) [50], a finding confirmed
by Shan et al. [51]. Moreover, these authors have shown
that the level of PRR expression in the SON was
higher in SHRs compared with Wistar–Kyoto control
animals, and that neuronal cells of SHRs have a higher
susceptibility to prorenin stimulation and displayed a
50 % higher ERK1/2 phosphorylation in response to
prorenin. A down-regulation of PRR expression in the
SON of SHRs by local injection of an adenovirus coding
for PRR shRNA (small-hairpin RNA) reduced the agedependent increase in BP in SHRs [51]. Importantly,
Hirose et al. [52] provided the first human data supporting
the role of PRR in the control of BP by showing
that the polymorphism IVS5+169T in the PRR gene
was associated with significantly higher systolic and
diastolic BP in a cohort of Japanese males, a result
recently confirmed by another study in Caucasians [53].
When aliskiren, a renin inhibitor, was made available
in clinics, it became important to determine its effect
on the binding and activation of PRR by (pro)renin.
All of the studies concluded that renin and prorenin
with the active site blocked by aliskiren still bound to
PRR and activated intracellular signalling [12,54] and,
conversely, aliskiren was able to inhibit PRR-bound
renin and prorenin [10,55]. In other words, aliskiren
has no effect on the binding and activation of PRR
by (pro)renin. Nevertheless, hypertensive diabetic rats
treated with aliskiren had a significant down-regulation
in PRR expression in the kidney [56]. However, the
mechanisms underlying this effect of aliskiren are still
not clear. This could be due to the (pro)renin repression
of PRR expression via the PLZF pathway or to the
inhibition of AngII generation by aliskiren, as a study
has shown that treatment of diabetic rats with valsartan
was also able to reduce PRR expression [41]. It would
be interesting to compare the effects of a renin inhibitor
and an ARB (AT1 R blocker) on the expression of PRR
in vivo.
THE MANY MOLECULAR FORMS OF PRR
All of the results and conclusions of studies in cells
in culture or in animals were based on PRR being
considered exclusively as an integral membrane protein
and acting as the receptor of renin and prorenin. However,
recent data have now shown that these assumptions were
wrong, because PRR exists in three different molecular
forms that may have different functions and that PRR
is also essential for a process completely independent of
renin and prorenin, namely the Wnt signalling pathway
(Figure 1).
The soluble form of PRR
PRR is a small protein of an apparent molecular mass of
35–39 kDa organized into a large EC (extracellular) domain, a single TM domain and a short IC (intracellular)
domain (Figure 2). The truncated form of PRR initially
described to be associated with the V-ATPase in bovine
chromaffin granules [57] is composed of the TM–IC
domains and a short portion of the EC domain, cleaved
at a close vicinity of a putative furin-cleavage site
(RKTR). The existence of the truncated TM–IC form of
PRR suggested that another truncated form composed
of the EC must exist. By analysing the conditioned
medium of cultured cells, we have demonstrated the
existence of a low-molecular-mass 28 kDa PRR [4]. Sitedirected mutagenesis of the furin-cleavage site and the use
of a furin-specific protease inhibitor abolished the
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Figure 1 Processing of PRR
(a) Furin cleavage in the trans -Golgi. (b) Vesicles containing the three molecular forms of PRR: (i) an integral membrane protein associated with the V-ATPase, (ii) a
truncated form associated with the V-ATPase and (iii) the sPRR. (c) The PRR–V-ATPase–LRP–Fz–Wnt complex. C-ter, C-terminus; N-ter, N-terminus.
generation of the 28 kDa PRR by cells in culture, whereas
inhibitors of metalloproteases, ADAM17 (a disintegrin
and metalloproteinase 17) and TNF-α protease had no
effect, confirming furin as the enzyme responsible for the
generation of the 28 kDa PRR. As this molecular form
of PRR was found in the conditioned medium, it was
named sPRR. Most importantly, sPRR could be found in
plasma, where it is able to bind renin [4], and also in urine
[58]. The role of sPRR has not been elucidated yet and we
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do not know whether it can increase renin activity and
activate prorenin as is the case for membrane PRR, or if
sPRR behaves as a circulating antagonist of membrane
PRR. An ELISA for sPRR will be available soon and
this will allow us to measure sPRR concentrations in the
plasma and urine of patients. The study of the variations
in sPRR in different types of pathologies might help
us to better understand the pathophysiology of PRR
and, for example, it would be of utmost interest to see
Renin, (pro)renin and receptor: an update
Figure 2 Organization of the multi-complex PRR–V-ATPase–LRP–Fz on the plasma membrane (a), and a schematic structure
of the three molecular forms of PRR (b)
C-ter, C-terminus; N-ter, N-terminus.
whether IVS5+169T in the PRR gene, associated with
higher ambulatory BP, is also associated with increased
levels of sPRR.
PRR associated with the V-ATPase
A multi-species protein sequence comparison revealed
homologues with the human PRR in most, if not all,
species including rat and mouse, and also chicken, frog,
zebrafish, mosquito and Drosophila, and species remotely
related to humans such as Caenorhabditis elegans (WormBase gene ID WBGene00010993; www.wormbase.org)
and the bacterium Ehrlichia chaffeensis [60], with the
highest homology being in the TM–IC region [2,3].
The truncated TM–IC form of PRR was identified by
chance when Ludwig et al. [57] were looking for proteins
associated with the V-ATPase (Figure 1).
V-ATPases are ATP-dependent proton pumps that
acidify intracellular compartments and transport protons
across plasma membranes in intercalated cells, osteoclasts, macrophages and tumour cells. The structure of
the V-ATPase is well established: they are multi-subunit
proteins composed of a V1 domain containing eight
different subunits (A–H), which is responsible for ATP
hydrolysis, and a V0 domain composed of six different
subunits (a, c, c , d, e and the accessory protein subnit Ac45 in mammals), which is responsible for proton
translocation (Figure 2). Some subunits in the V1 and
V0 domains may be present in multiple copies and
most subunits have tissue-specific isoforms [61,62]. In
mammals, there are two accessory subunits binding to the
V0 sector that have been described to regulate V-ATPase
activity: Ac45 encoded by the gene ATP6ap1 and the
truncated form of PRR encoded by the gene APT6ap2. If
Ac45 is a genuine accessory protein, because it is found
as an integral component of the V0 sector, and therefore
deserves to be named a V-ATPase subunit [63], PRR is
mistakenly considered and named a V-ATPase subunit
because it has never been found as an integral component
of the V0 sector. However, Ac45 and PRR share some
similarities. First, they are processed by furin. This furin
processing appears to be a prerequisite for Ac45 function,
as reduced proteolytic processing of Ac45 impairs acidic
vesicle formation and is responsible for defective insulin
secretion in pancreatic β-cells [64]. This could explain
why the majority of PRR is also cleaved by furin [4] to
generate the truncated TM–IC necessary for V-ATPase
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assembly. Secondly, ATP6ap1/Ac45 knockout in mice is
embryonic-lethal [65] and PRR-knockout mice could not
be generated. Thirdly, mutation of ATP6ap1/Ac45 and
ATP6ap2/PRR in zebrafish gives a similar phenotype:
oculocutaneous albinism, small head and eyes, CNS
(central nervous system) necrosis and embryonic lethality
[66,67].
There is only one known human mutation for the accessory proteins Ac45 and PRR, and it is in the ATP6ap2/
PRR gene encoding PRR and is responsible for
X-linked mental retardation, epilepsy and ataxia without
cardiovascular or renal dysfunction [68]. The silent
mutation is in an exon splicing enhancer site, resulting
in the inefficient inclusion of exon 4 in 50 % of the
mRNA and hence the synthesis of full-length and of
exon 4-deleted PRR. Mutant PRR behaves as a dominantnegative, impairing ERK1/2 activation induced by renin
and inhibiting neuronal differentiation of PC12 cells
stimulated by NGF (nerve growth factor) [50]. We
attributed the X-linked mental retardation to impaired
NGF-induced neuronal maturation, but in light of the
recent data on the role of PRR in Wnt signalling and
CNS patterning in Xenopus embryos [69], the possibility
of a defective interaction of exon 4-deleted PRR with
Fz (frizzled) and impaired Wnt signalling is highly
conceivable.
Consistent with an important role in the CNS, we
have shown that PRR is highly expressed in neurons
and on plasma membranes, where it binds renin and
mediates ERK1/2 phosphorylation [50,70], but it is also
present in synaptic vesicles, where V-ATPase is essential
for neurotransmitter concentration and maturation,
suggesting again a link between PRR and V-ATPase. A
functional link between PRR and V-ATPase has been
suggested for the first time in renal cells. The membrane
V-ATPase found at the luminal side of intercalated cells of
the late distal tubule and collecting duct is responsible for
acid secretion into the urine. To no surprise, intercalated
cells are also rich in PRR that co-localizes with the
V-ATPase, and Advani et al. [71] have shown that
blocking V-ATPase function with bafilomycin in MDCK
(Madin–Darby canine kidney) cells of a collecting
duct/distal lineage also inhibited PRR activation and ERK
phosphorylation induced by (pro)renin, thus establishing
a possible link between PRR and V-ATPase. Recently,
Kinouchi et al. [72] have generated mice with specific
ATP6ap2/PRR-knockout in cardiomyocytes by crossing
ATP6ap2/PRR-floxed mice with mice expressing Cre
recombinase under the control of the α-MHC (αmyosin heavy chain) promoter. The affected males
ATP6ap2/PRRflox/Y ×α − MHC-Cre+/0 are born, but the
mice die within 3 weeks from severe heart failure. The
histological alterations included large fibrotic areas and
degenerative cardiomyocytes. These cardiomyocytes had
disorganized fibrillar structures, excessive vacuoles and
were congested by autophagic vacuoles, a phenotype that
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could be reproduced by treating normal cardiomyocytes
with bafilomycin. These authors also showed that
deletion of ATP6ap2/PRRflox/Y ×α − MHC-Cre+/0 in
fibroblasts isolated from ATP6ap2/PRRflox/Y mice
resulted in the down-regulation of all subunits of
the V0 sector, whereas the subunits of the V1 sector
were unaffected [72]. These in vitro data confirm
the importance of ATP6ap2/PRR in the assembly
and function of the V-ATPase, as do the phenotype
of PRR-knockout mice. Whether the phenotype of
PRR-knockout mice is solely attributable to V-ATPase
dysfunction is certainly a hasty conclusion, as it is
well known that Wnt signalling is essential for cardiac
development and differentiation [73] and that altering
ATP6ap2/PRR must have affected Wnt signalling and
function independent of V-ATPase.
PRR associated with LRP (low-density
lipoprotein receptor-related protein)/Fz
and involved in Wnt signalling
As is so often the case, the most unexpected data
on the function of PRR were reported by a group
not working in the cardiovascular or renal field, but
in embryonic development, who showed an absolute
requirement for PRR in the Wnt/β-catenin signalling
pathway [69]. The Wnt proteins are growth factors and
their signalling is fundamental for a normal patterned
embryo. In the adult, Wnt signalling is involved in cell
proliferation, migration and polarity, and abnormal Wnt
signalling is known to promote human degenerative
diseases including cancer. The Wnt proteins refer to a
family of structurally related secreted, although highly
hydrophobic, proteins. Wnt proteins act on target cells
by binding to a complex formed of Fz, their primary
receptor containing a seven-transmembrane region, and
LRP, a single-pass transmembrane protein (Figure 2). The
members of the Wnt family can activate different highly
interconnected signalling pathways, and these signalling
pathways are subdivided into the canonical Wnt/βcatenin-dependent pathway and several non-canonical
Wnt signalling pathways not involving β-catenin. Among
the non-canonical pathways, one is called the Wnt/PCP
(planar cell polarity) signalling pathway with regard to a
mechanism similar to the Drosophila PCP, a process that
allows cell to polarize in the plane of a tissue and which is
complementary to their apical–basal orientation. As the
present review is not intended to cover Wnt signalling,
we direct readers to some excellent reviews by specialists
in the Wnt signalling field [73–77].
The first relationship between PRR and Wnt was
published by Cruciat et al. [69], who were looking
for proteins involved in the regulation of canonical
Wnt/β-catenin signalling. The authors took a genomewide siRNA (small inhibitory RNA) screening approach
in HEK-293T cells (human embryonic kidney cells
Renin, (pro)renin and receptor: an update
expressing the large T-antigen of simian virus 40) and
used a Wnt-responsive luciferase reporter assay as a readout. PRR was then identified as an adaptor between the
Wnt receptor complex and the V-ATPase, and the results
indicated that endocytosis of LRP5/6 was necessary for
its phosphorylation and downstream β-catenin activation
[69]. This function of PRR requires the EC and TM, but
not the cytoplasmic domain, and the authors showed
that the EC domain of PRR bound to LRP5/6 and
Fz (Figure 1). When PRR antisense morpholinos were
injected into Xenopus embryos, the tadpoles had smaller
heads and a defect in melanocyte and eye pigmentation, a
phenotype very similar to that of ATP6ap2/PRR-mutant
zebrafish embryos [66,67]. Because the expression of PRR
was prominent in the CNS of Xenopus, the authors
performed a detailed study of the CNS in Xenopus
embryos injected with PRR antisense morpholinos and
found a defect in the anterio–posterior neural patterning.
Shortly after, Hermie et al. [78] and Buechling
et al. [79] simultaneously confirmed that the Drosophila
homologue of PRR binds to the Fz receptor in not
only in the Wnt/β-catenin pathway, but also in the
Wnt/PCP pathway, thus regulating two major processes:
planar polarity in Drosophila and convergent-extension
movements in Xenopus gastrulae. The implication of
these observations is huge, because PCP is an absolute
requirement for most if not all cell types to function
properly. In adult tissue, the typical illustrations of
the role of PCP in vertebrates are feathers in birds
and hair in mammals. During embryonic development,
PCP signalling is necessary for the convergent-extension
of mesenchymal cells during gastrulation and neural
tube cells during neurulation, a process where cells
move towards the midline and intercalate, allowing
extension of the body axis. In the renal field and
during kidney development, PCP signalling is tightly
linked to ciliopathies and therefore to polycystic
kidney disease [80]. It is important to stress that the
function of PRR in the Wnt/β-catenin and Wnt/PCP
signalling pathways is totally independent of renin,
as renin is not expressed in Xenopus embryos at
the early phase of development where the study was
performed, and Drosophila and Hydra do not have
renin.
These studies showing the involvement of PRR in Wnt
signalling during embryonic development are extremely
exciting and they probably explain why no PRRknockout mice have ever been generated. However, we
should also keep in mind that Wnt signalling is important
in adult stem cell biology, especially in the field of
degenerative diseases and cancer. We have reported a
high level of expression of PRR in human glioblastoma
and have shown that inhibition of renin activity in
glioblastoma cells reduced their proliferation rate and
induced apoptosis [81]. Now, with this new development
in PRR biochemistry, it would be interesting to correlate
PRR expression and the degree of Wnt/β-catenin
signalling activity in these glioblastoma cells.
CONCLUSIONS AND PERSPECTIVES
In 2006, at the Gordon Conference on angiotensins,
4 years after its first description, we predicted that
PRR was a multi-functional protein on the basis of
the observation that its wide tissue distribution in adult
and enormous expression in embryonic mouse did not
fit with a function restricted to the RAS. There is
now accumulating evidence that this is indeed true and
that PRR is involved in V-ATPase function and in the
Wnt receptor complex signalling. The newly discovered
function of PRR in the Wnt signalling pathways adds a
new dimension to the study of the pathological relevance
of PRR and is taking us from organ damage and fibrosis in
hypertension and diabetes to the biology of embryonic
stem cell and development, and of adult stem cell and
tissue repair and cancer [82]. Although the new aspects
of PRR as an accessory subunit of the V-ATPase and a
cofactor of the Wnt receptor complex are really exciting,
we must keep in mind that the human data available so far
establish a link between ATP6ap2/PRR and higher BP in
the case of the IVS5+169T polymorphism and to altered
neuronal function due to the silent 321C > T mutation.
Two major advances have been made that will help us
understand the functions of PRR: (i) the generation of
ATP6ap2/PRR-floxed mice that allow the embryonic
lethality due to total ablation during development to
be overcome to enable the study of PRR in adult mice
in disease models, and (ii) an ELISA to measure sPRR.
We predicted in a recent review [5] that tissue-specific
knockout of PRR would give surprising results and we
were indeed right. The phenotype of animals lacking PRR
in cardiomyocytes is totally unexpected, with massive
cardiac defects attributed to impaired V-ATPase assembly
and defective autophagy, once again totally ignoring the
complexity of PRR functions and its role of PRR in Wnt
signalling and the importance of Wnt signalling in cardiac
development. In 2010, recombinant full-length PRR or
sPRR still remains to be produced, which would
allow the crystal structure to be solved and be of
use in studying the function of the soluble receptor.
Nevertheless, we believe that animal studies, if carefully
examined and interpreted in light of the many functions
of PRR, will be able to give us clues as to the role of PRR
in pathology. Then, the fact that PRR is a receptor with a
soluble counterpart might make it a valuable therapeutic
target not only in cardiovascular and renal disease, but
also in degenerative diseases.
ACKNOWLEDGEMENT
I thank France Maloumian for her expert assistance in
preparing the illustrations.
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G. Nguyen
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Published on the Internet 19 November 2010, doi:10.1042/CS20100432
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