THOROUGH CRITICAL APPRAISAL
www.sin-italy.org/jnonline – www.jnephrol.com
Potential role of the (pro)renin receptor
in cardiovascular and kidney diseases
Christelle Cousin, Diane Bracquart,
Aurelie Contrepas, Geneviève Nguyen
Abstract
The discovery of a (pro)renin receptor ((P)RR) and the
introduction of renin inhibitors in the clinic has brou-
ght prorenin, the inactive proenzyme form of renin,
back into the spotlight. The (P)RR binds both renin
and its inactive precursor prorenin, and their binding
triggers intracellular signaling that up-regulates the
expression of profibrotic genes. Furthermore, bin-
ding of prorenin unmasks its active site and endows
prorenin with angiotensin I–generating activity. Many
studies have attempted to establish a link between (P)
RR and hypertension, (P)RR and tissue fibrosis asso-
ciated with hypertension and with diabetic nephropa-
thy. Models of transgenic rats overexpressing (P)RR
develop high blood pressure and have glomeruloscle-
rosis, suggesting a link between increased (P)RR and
these pathologies, but no definite proof of any role of
(P)RR in other models of cardiovascular or renal di-
seases could be established because of the absence
of any specific (P)RR antagonist and of tissue-specific
(P)RR null mice. Nevertheless, a study in a large co-
hort of Japanese men has shown a correlation betwe-
en a polymorphism in the (P)RR gene and increased
ambulatory blood pressure. Finally, a mutation in the
(P)RR gene is responsible for mental retardation and
epilepsy, indicating that (P)RR is essential during brain
development.
Key words: Diabetes, Fibrosis, Hypertension, Mental
retardation, (Pro)renin receptor
508 © 2010 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2010; 23 ( 05 ) : 508-513
Inserm Unité 833 and Collège de France, Paris - France
Introduction
The renin-angiotensin system (RAS) is mostly studied for
its role in the control of blood pressure and salt balance.
During the last decade, the RAS has shown new faces,
new components were discovered and the involvement of
the RAS in many other essential pathophysiological pro-
cesses such as development, inflammation and remode-
ling was emphasized. The discovery of a specific receptor
for renin and prorenin and the clinical development of a
renin inhibitor have further stimulated interest in the RAS
and for the optimization of the RAS blockade.
The classical RAS is a cascade of enzymatic reactions:
angiotensinogen (Aogen) is cleaved by renin to generate
angiotensin I (Ang I) converted in Ang II by the angiotensin-
converting enzyme (ACE), and Ang II is considered to be
the main biologic active peptide through binding to its AT1
and AT2 receptors (Fig. 1). Renin is an aspartyl protease
synthesized and secreted as an inactive proenzyme, pro-
renin, characterized by a 43 amino acid prosegment that
covers the cleft of the active site. Prorenin maturation into
renin is due to the cleavage of the prosegment, a process
that takes place exclusively in the myoepithelioid cells of
the juxtaglomerular apparatus (JGA) in the kidney where
renin is stored in secretory granules and released in pla-
sma under various stimuli (1), whereas many other tissues
synthesize and secrete prorenin (2-4). The term (pro)renin
designates both renin and prorenin.
The existence of a tissue RAS and of a receptor for renin was
postulated long ago based on 2 observations: most plasma
 JNEPHROL 2010; 23 ( 05 ) : 508-513

Fig. 1 - Schematic representation

of the classical renin-angiotensin
system (RAS) and its emerging
pathway supported by the (pro)
renin receptor. Overactivation of
the classical RAS may lead to
organ damage by angiotensin II
receptor type 1 activation. Renin
and prorenin activate (P)RR and
trigger intracellular signaling. In
addition, the binding of prorenin
provokes its non-proteolytic acti-
vation. The consequences of this
Ang II–independent pathway on
organ damage are not yet esta-
blished. ACE = angiotensin-con-
verting enzyme; Ang I = angio-
tensin I; Ang II = angiotensin II;
Aogen = angiotensinogen; AT1-R
= angiotensin II type-1 receptor;
ERK1/2 = extracellular regulated
kinase 1/2; HSP27 = heat shock
protein-27.

Fig. 2 - Schematic representation

of the (pro)renin receptor – the
(P)RR. The (P)RR is composed
of 3 domains: extracellular, tran-
smembrane and cytoplasmic do-
mains. It is cleaved by furin to ge-
nerate a soluble fragment called
soluble (pro)renin receptor (s(P)
RR) released in the plasma and
the M8.9 transmembrane and
cytoplasmic fragment. The frag-
ment M8.9 is highly conserved
in vertebrates and invertebrates,
whereas s(P)RR is only conser-
ved in vertebrates.

Ang II originates from tissue where it is generated, and a lo-
cal Ang II synthesis exists in tissues such as the brain, heart,
eye, adipose tissue and kidney in the absence of local matu-
re renin production, suggesting active renin uptake likely by
receptor (5-8). Several binding sites and receptors for renin
and for prorenin were described (2), but this review will fo-
cus on the specific (pro)renin receptor called (P)RR and on
its potential role in disease.
Biochemistry
Structure of (P)RR
Using 125I-labeled renin Nguyen and colleagues have
identified a binding site specific for renin and prorenin
in human mesangial cells (9). The receptor was cloned
in 2002 by screening a human kidney expression libra-
ry (10), and called (P)RR, for (pro)renin receptor since
it bound renin and prorenin. (P)RR is a 350 amino acid
protein without homology with any known protein, and
the gene called ATP6AP2 (see below) is located on the X
chromosome at the p11.4 locus. (P)RR binds renin and
prorenin with an affinity in the nanomolar range (10).
(P)RR is a single transmembrane domain receptor and
has a large extracellular domain responsible for (pro)re-
nin binding, and a short cytoplasmic domain of 20 amino
acids (Fig. 2). (P)RR also exists in a soluble form gene-
rated by intracellular cleavage by furin, and this soluble
form can be found in plasma and is able to bind renin
(11). The existence of the soluble form of (P)RR supports
the initial finding of a 10-kDa truncated (P)RR encompas-

509
Cousin et al: (Pro)renin receptor and diseases
sing the transmembrane and cytoplasmic domains and
coprecipitating with vacuolar proton-ATPase (V-ATPase)
in bovine chromaffin granules (12). This also explains
the reason why the (P)RR gene was called ATP6AP2 (for
ATPase accessory protein 2). V-ATPase is essential in
the acidification and control of cellular pH, and (P)RR
and V-ATPase were shown to colocalize in the brush bor-
der of collecting duct distal tubular cells (13). The exact
meaning of this colocalization of (P)RR with V-ATPase is
not yet fully understood (14).
The domains of (P)RR interacting with (pro)renin have not
been identified yet, but it is now established that the active
site is not involved in the interaction, since renin inhibitors
have no effect on (pro)renin binding to (P)RR (15). Very
little is known about the regulation of expression of (P)RR
except about the negative control of renin and prorenin on
their own receptor expression, which was demonstrated
in vitro in cell cultures (16, 17).
Effects of (pro)renin binding to (P)RR, and of (P)
RR activation
The binding of (pro)renin to (P)RR has 2 major consequen-
ces: (i) the nonproteolytic activation of prorenin, and (ii) the
activation of intracellular signaling involving the MAP kina-
ses ERK1/2 and p38 pathways.
Prorenin nonproteolytic activation
Prorenin can be activated in 2 ways: in a proteolytic and
a nonproteolytic manner. Proteolytic activation is due to
the cleavage of its prosegment, a process that uncovers
irreversibly the active site. This only occurs in the myo-
epithelioid cells of the JGA in the kidney (2). A nonpro-
teolytic activation can be observed in vitro at acidic pH
or low temperature. During this process, the prosegment
moves, uncovering the active site of prorenin, but this
process is reversible, and the prosegment can return to
its original conformation, closing again the active site
cleft. This dynamic process is believed to occur also in
plasma, and in normal conditions, 2% of circulating pro-
renin is in the open conformation form. Nonproteolytic
activation is also likely to occur when prorenin is bound
to (P)RR.
In normal subjects, prorenin represents up to 90% of
total plasmatic renin. In pregnant women and diabetic
patients, this prorenin to renin ratio can reach 95% (18).
The reason for high prorenin levels in diabetic patients
is still unknown. Prorenin levels were correlated with
nephropathy and retinopathy (19), and it was even pro-
510
posed that prorenin was as predictive marker of micro-
vascular complications (20). The existence of a prorenin
uptake (21) and of prorenin enzymatic activity was su-
spected long ago (22) and elegantly demonstrated by
Methot et al (23). These authors have generated double
transgenic mice expressing human angiotensinogen
and human prorenin either native or noncleavable pro-
segment prorenin, in the pituitary gland of the animals,
and they analyzed the content of pituitary Ang I. With
regard to the species-specificity of the RAS, any incre-
ased of Ang I in the pituitary gland would reflect human
Aogen cleavage by human renin. Their results showed
an increased of Ang I in the pituitary gland of animals
transgenic for Aogen and native prorenin and for Aogen
and noncleavable prorenin compared with single tran-
sgenic animals expressing Aogen only, thereby demon-
strating the existence of a local enzymatic activity of
prorenin in vivo (23). A possible binding and activation
of human prorenin to mouse (P)RR may explain the lo-
cal prorenin activation, as it has been recently shown
that (P)RR was widely and highly expressed in mouse
brain (24).
Intracellular signaling triggered by (P)RR activation
The binding of (pro)renin induces (P)RR phosphorylation
on serine and tyrosine residues and MAP kinase ERK1/2
activation (10), which in turn up-regulates profibrotic mo-
lecule (TGFβ, PAI-1, collagen I and fibronectin) expres-
sion and cell proliferation (10, 25, 26), and these effects
are not abolished by ACE inhibitors or by AT1 receptor
antagonists, indicating that they are not dependent on
Ang II generation. In cardiomyocytes, (P)RR activation
leads to p38 and heat shock protein-27 (HSP27) phos-
phorylation, known to be involved in actin polymeriza-
tion and cell motility (27). Interestingly, transgenic rats
overexpressing hepatic prorenin have renal lesions and
severe cardiac hypertrophy but normal blood pressure
and normal plasmatic Ang II (28). These observations
suggest that prorenin might play a role in the pathoge-
nesis of fibrosis by binding to (P)RR and activating intra-
cellular signaling. However, glomerulosclerosis was not
observed in transgenic ren-2 rats with inducible prorenin
expression, despite 200-fold higher prorenin levels fol-
lowing induction (29), nor was cardiac fibrosis or glome-
rulosclerosis observed in transgenic mice overexpres-
sing native prorenin or active site–mutated prorenin (30).
From these experimental models, it can be concluded
that prorenin increase per se cannot be considered as a
primary determinant of fibrosis.

(P)RR in pathophysiology: what have
we learned from the animal models?
Some evidence that (P)RR might be related to cardio-
vascular diseases comes from studies with transgenic
rats with (P)RR overexpression. When human (P)RR is
overexpressed ubiquitously, the transgenic rats are nor-
motensive, but develop proteinuria and slowly progressi-
ve nephropathy, suggesting a direct pathological role of
(P)RR in renal damage. The glomeruli of transgenic rats
showed increased ERK1/2, p38 and JNK, but not EGFR
phosphorylation, compared with controls, and renal Ang
II was normal (31). Rats overexpressing the human (P)RR
exclusively in smooth muscle cells, including vascular
smooth muscle cells ¸develop a cardiovascular phenot-
ype after 6 months of age, with elevated systolic blood
pressure and augmentation in heart rate, but their kidney
function was normal, and there was an increase in plasma
aldosterone and in aldosterone to renin ratio (32). Different
levels of transgene expression may have accounted for
the different phenotypes. In this model, the vascular ex-
pression was not dramatically elevated in the kidney and
therefore probably not sufficient to induce proteinuria and
glomerulosclerosis. However, smooth muscle cell (P)RR
transgenic rats showed very high levels of expression of
the transgene in the lung, they increased their respiratory
rate with age, and this could have contributed to the rise
in blood pressure. From these models of overexpression,
evidence that (P)RR is related to cardiovascular disease is
currently not very strong.
In a Goldblatt model of hypertension, the parallel increases
in (P)RR and renin have been suggested to be profibrotic in
the clipped kidney (33); also, increased (P)RR synthesis was
shown in the kidney of diabetic rats (34).
There are 2 means to demonstrate the role of a receptor in
disease: the prevention of the disease by a specific (P)RR
antagonist or by ablation of (P)RR gene expression. There is
no ideal (P)RR blocker at the moment except a peptide, the
effects of which are highly controversial (35), and unfortuna-
tely (P)RR knock-out mice are not available yet.
Unexpected properties of the (P)RR
In rodents, (P)RR gene expression is ubiquitous and starts
very early in development, whereas renin expression can
be detected in large intrarenal arteries only at 15.5 days
of gestation (36), suggesting that the (P)RR has functions
that might be unrelated to the RAS. Analysis of the sequen-
ce of (P)RR coding cDNA shows that sequence coding for
JNEPHROL 2010; 23 ( 05 ) : 508-513
the transmembrane and the intracellular domain putative-
ly associated with the V-ATPase is remarkably conserved
between invertebrates and vertebrates, whereas the cDNA
sequence coding for the extracellular domain responsible
for renin and prorenin binding is conserved in vertebrates
only (37, 38). This leads to the postulate that the (P)RR gene
may result from the fusion of 2 genes – an ancient gene
(corresponding with the C terminus) coding for a protein
essential for cell survival, and a more recent gene in ver-
tebrates (corresponding with the N terminus) which binds
renin and prorenin.
Conclusion and perspectives
Although studies on the (pro)renin receptor have allowed
a better understanding of the biochemistry of the recep-
tor, arguments supporting a role of (P)RR in diseases are
lacking because of the absence of a specific (P)RR anta-
gonist and of (P)RR knockout mice, making the generation
of (P)RR floxed mice a mandatory step in the study of (P)
RR functions. But there is one situation in which the impor-
tance of (P)RR cannot be disputed, and that is during brain
development and neuronal maturation, because the only
known mutation in the (P)RR gene is responsible for mental
retardation and epilepsy (39), and because a recent study
has shown that the mutated (P)RR can affect neuronal cell
differentiation (24).
Financial support: C.C. is funded by a CIFRE contract with Institut
de Recherche Servier. D.B. is funded by Conseil Regional de l’Ile
de France.
Conflict of interest statement: None declared.
Address for correspondence:
Geneviève Nguyen, MD, PhD, FAHA
Institut de la Santé et de la Recherche Médicale
(INSERM) Unit 833 and Collège de France
Experimental Medicine Unit
11 place Marcelin Berthelot
FR-75005, Paris, France
genevieve.nguyen@college-de-france.fr
511
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Received: September 11, 2009
Accepted: December 10, 2009
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