Susceptibility to hypertensive renal injury mediated by P2X receptors
Menzies, Robert Ian
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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.