REGULATION OF THE RENAL ANGIOTENSIN-II RECEPTOR GENE IN ACUTE UNILATERAL URETERAL OBSTRUCTION

We have shown that acute (24-hr) unilateral ureteral obstruction (UUO) induces the genes encoding for renin, in juxtaglomerular apparatuses and in tubules, for angiotensin converting enzyme in vascular endothel ial cells, and for angiotensinogen in perivascular fat. These molecula r changes occur in temporal association to marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR), suggesting that angiotensin II (Ang II) is at least partly responsible for the renal vasoconstriction. We tested the hypothesis that down-regulation of the Ang II type-1 receptor (AT(1)-R) gene occurs in UUO in response to An g II, by examining the effects of an ACE inhibitor [lisinopril (Li), 5 mg/kg/day] and of the specific nonpeptidic AT(1)-R blocker, losartan (Lo) (10 mg/kg/day). UUO or sham operated (which included manipulation but not obstruction of the ureter) rats (S) were studied. Northern bl ot analysis of the steady state concentration of AT(1)-R mRNA correcte d for GAPDH mRNA showed a marked decrease in receptor expression (-77% , N = 4, P < 0.01) in the obstructed kidney (UUO) compared to S; sham diminished gene expression modestly compared to the contralateral kidn eys (C) of UUO. In situ hybridization for AT(1)-R mRNA also showed dim inished expression in UUO compared to C kidneys (N = 4). Treatment of UUO rats (N = 4) with Lo increased AT(1)-R mRNA five times above the l evels in UUO rats receiving vehicle; the increase induced by Li was 50 % that of Lo; S (N = 4) and C (N = 4) did not change. Losartan, but no t vehicle treatment increased RBF (sixfold) and GFR (fivefold) in the UUO kidneys. We conclude that UUO leads to down-regulation of AT(1)-R mRNA, and that this effect is mediated by Ang II, which is also respon sible for a major component of the renal hemodynamic changes. Some fun ction of UUO or ureteral manipulation, possibly stretch or nerve stimu lation, differentially regulates the genes encoding for the renin-angi otensin system in the kidney.