NDT Advance Access originally published online on October 19, 2007
Nephrology Dialysis Transplantation 2007 22(11):3128-3130; doi:10.1093/ndt/gfm614
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Angiotensin AT1 and AT2 receptors—the battle for health and disease
Helmy M. Siragy
Department of Medicine and Hypertension Center, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, VA 22908, USA
Correspondence and offprint requests to: Dr Helmy M. Siragy, P.O. Box 801409, University of Virginia Health System, Charlottesville, VA 22908-1409, USA. Email: hms7a{at}virginia.edu
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Influence of angiotensin AT1 and AT2 subtype receptors on functional molecules of glomerular slit diaphragm
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Proteinuria is associated with progression to end stage renal
disease. The exact mechanisms contributing to the development
of this pathological condition are yet to be elucidated. In
the June issue of the
American Journal of Pathology, Suzuki
et al. [
1] investigated the role of angiotensin II (Ang II)
type 1 (AT1) and type 2 (AT2) receptors in regulating the barrier
functions of the slit diaphragm, a component of a filtration
barrier of the kidney glomerulus, which prevent the leak of
plasma proteins into urine. Both
in vivo and
in vitro studies
were performed in female Brown Norway rats and in immortalized
mouse podocytes. Rats developed proteinuria by the induction
of nephropathy post-anti-nephrin antibody (ANA) administration.
The development of nephropathy was based on ANA down-regulation
of the slit diaphragm functional molecules. In this animal model,
there was an increase in the expression of AT1 and AT2 receptors
together with a decreased expression of nephrin, podocin and
ZO-1. These results were supported by the increase in the copy
number of AT1 and AT2 receptors' mRNA. Importantly, these changes
correlated with the proteinuric state. The expression of the
glomerular AT1 and AT2 receptors was localized mainly in the
podocytes. AT1 receptor blockade ameliorated the proteinuria
caused by a reduction in the functional molecules of slit diaphragm,
mainly the reduction of nephrin and podocin. Although AT2 receptor
blockade did not influence these proteins, stimulation of the
AT2 receptor enhanced their expressions. These results were
confirmed in cultured podocytes, where Ang II reduced nephrin
mRNA, an effect that was reversed by AT1 receptor blockade and
AT2 receptor stimulation. The fact that animals lacking the
AT2 receptor do not develop nephropathy positions the AT1 receptor
as the primary receptor that contributes to the development
of kidney disease. It would be interesting to repeat these studies
in the AT2 receptor knockout mice and evaluate whether these
animals are more susceptible to the development of this type
of nephropathy. It is possible that AT2 receptor protective
function is induced when there is a renal injury and this effect
would not be necessary obvious in absence of renal pathology.
These results demonstrate the potential for the development
of a new therapy to treat proteinuria based on AT2 receptor
stimulation.
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Glomerular slit diaphragm
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Structurally glomerular endothelial cells, glomerular basement
membranes
(GBM) and podocyte foot processes form glomerular capillary wall. Glomerular slit diaphragm is a membrane-like structure that connects foot processes of different cells including podocytes and functions as a barrier that prevents leakage of plasma proteins into urine. Several molecules were described as components and regulators of the functions of the slit diaphragm, mainly nephrin, podocin and CD2-associated protein.
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Angiotensin AT1 and AT2 receptors cross talk
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Ang II is involved in the development of kidney diseases, leading
to increased morbidity and mortality. Past studies have provided
convincing evidence that interruption of the renin–angiotensin
system (RAS) through the use of angiotensin-converting enzyme
(ACE) inhibitors or AT1 receptor blockers improve the renal
outcome [
2–10]. The exact mechanism of the contribution
of the RAS to the development of kidney disease is not well-established.
All components of the RAS are present in the kidney [
11]. The
concentration of Ang II in the renal proximal tubules and interstitial
fluid is approximately 1000 times the concentration in plasma.
Angiotensin receptor subtypes AT1 and AT2 have also been localized
in the kidney [
12]. Angiotensin AT1 receptors are present in
the renal vasculature, glomerular mesangium, interstitial cells
and proximal tubules, while AT2 receptors have been localized
at the renal vessels, glomeruli and tubules. AT1 receptor, a
G-protein coupled receptor, is the principal Ang II receptor
and is linked to the development of a variety of renal and cardiovascular
diseases. It is well-established that AT1 contributes to such
pathological conditions by the stimulation of cellular growth
via protein phosphorylation, which in turn activates DNA transcription
of several cytokines and growth mediators such as TNF
and TGF-β.
Unlike AT1 receptor, the AT2 receptor is coupled to various phosphatases and mediates protein dephosphorylation. AT2 receptor has several described functions related to the inhibition of cell growth, promotion of cell differentiation, and stimulation of apoptosis [10]. In addition, AT2 receptor stimulates the renal production of NO, bradykinin and cGMP [13–16].
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Potential clinical implications
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Although it is known that the AT1 receptor may contribute to
the development of kidney diseases, the mechanisms that lead
to these pathological conditions are not well understood. Furthermore,
it is not known if AT2 receptor plays any role in these diseases.
Similarly, the available data are not clear on the events that
mediate the development of nephropathy, in particular the changes
that are mediated by Ang II. Ang II stimulates bioactivation
and expression of TGF-β leading to renal hypertrophy and
accumulation of extracellular matrix proteins in the kidney.
Similarly, cytokines, including TNF
, have been implicated in
the development and progression of nephropathy. TNF
is stimulated
by Ang II and leads to the development of renal fibrosis [
17].
A study by Suzuki
et al. [
1] reports of an increased Ang II
production in animals treated with ANA and a developed reduction
in slit diaphragm functional molecules leading to proteinuria.
The mechanism involved in this process is mediated by AT1 receptor,
since its blockade restored the slit diaphragm functional proteins
and reduced the proteinuria. Is there a role for the AT2 receptor
in improving this pathological process? It is well-established
that AT2 receptor inhibits cell proliferation and matrix formation
[
11]. However, despite the availability of this information,
the potential therapeutic role of the AT2 receptor in nephropathy
is unknown. Previous studies demonstrated protective renal effects
for the AT2 receptors through enhancing renal vasodilation [
18]
and sodium excretion [
15]. Thus, renal localization of the AT2
receptor may determine its mechanisms that are involved in preventing
the development of kidney diseases. Presence of the AT2 receptors
in podocytes [
1] suggest their involvement in the regulation
of slit diaphragm functional molecules. This effect is confirmed
by the observation of enhanced expression of nephrin and podocin
during AT2 receptor stimulation. Thus, restoration of AT2 receptor
activity may protect against the development of renal morphologic
and functional changes seen during the development of nephropathy.
Similarly, stimulation of the AT2 receptor may be a potential
new therapeutic option for the management of renal diseases,
in particular with the recent evidence that this receptor inhibits
renin biosynthesis [
19,
20] and leads to a down-regulation of
the RAS activity. Additionally, the potential use of multiple
blockers of RAS such as AT1 receptor blockers and angiotensin
converting enzyme or direct renin inhibitors may add more therapeutic
efficacy to the management of kidney diseases. A recent study
[
21] suggests that the combination of the renin inhibitor, aliskiren
and the AT1 receptor blocker valsartan, at maximum recommended
doses provides significantly greater reductions in blood pressure
than does monotherapy with either agent.
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Acknowledgements
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This study was supported by grant DK078757 and HL091535 from
the National Institutes of Health to H. M. S., MD. Dr Siragy
was the recipient of the Research Career Development Award K04-HL-03006
from the National Institutes of Health.
Conflict of interest statement. None declared.
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References
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- Siragy HM, Inagami T, Carey RM. NO and cGMP mediate angiotensin AT2 receptor-induced renal renin inhibition in young rats. Am J Physiol Regul Integr Comp Physiol (2007) [Epub ahead of print].
- Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet (2007) 21(370):221–229.
Received for publication: 26. 7.07
Accepted in revised form: 14. 8.07
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