Susceptibility to hypertensive renal injury mediated by P2X receptors
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Date
02/2014Author
Menzies, Robert Ian
Metadata
Abstract
The renin angiotensin aldosterone system is the dominant hormonal
regulatory system controlling sodium balance and therefore blood pres-
sure homeostasis. Abnormal modulation of this system is implicated
in the pathogenesis of hypertension and end organ injury. We have
previously developed the Cyp1a1-Ren2 transgenic rat to model an-
giotensin II (ANG II) dependent hypertension. In this model hyper-
tension causes renal injury, predominantly in the preglomerular vas-
culature. The susceptibility to renal injury has a genetic component.
A consomic/congenic study identified angiotensin converting enzyme
(Ace) as an important modifer.
However, renal injury is unlikely to be in
uenced by a single gene. In
this thesis it was hypothesised that examination of a renal microar-
ray to compare the relative expression in F344 (susceptible) and Lewis
(relatively protected) strains would reveal further genetic factors me-
diating renal injury susceptibility. Genome wide expression analysis
confirmed that Ace was a key modifier gene. Furthermore, the puriner-
gic receptors P2x7 and P2x4 were identified as additional candidates.
Gene and protein expression of these P2X receptors were both higher
in F344 compared with Lewis. Immunohistochemistry localised P2X7
and P2X4 to the renal vasculature and tubules: the expression pattern
was similar in both strains but became distinct in the renal medulla.
F344, but not Lewis, responded to acute antagonism of P2X7 and
P2X4. F344 showed a significant drop in blood pressure but maintained
renal blood ow, indicative of tonic renal vasoconstriction. When
ANG II was infused into F344 rats, there was a modest increase in
blood pressure and an impairment of the pressure-natriuresis mecha-
nism but no overt injury. Blood oxygenation-level dependent magnetic
resonance imaging of the kidney identified a decrease in renal R2* sig-
nal following P2X7 and P2X4 antagonism in ANG II infused F344
rats. P2X7/4 receptor activation reduces oxygenation and suppresses
pressure-natriuresis. These effects are pro-biotic and may underpin
susceptibility to renal injury.
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