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 endothelial cells, and for angiotensinogen in perivascular fat. These molecular 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 (AT1-R) gene occurs in UUO in response to Ang II, by examining the effects of an ACE inhibitor [lisinopril (Li), 5 mg/kg/day] and of the specific nonpeptidic AT1-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 blot analysis of the steady state concentration of AT1-R mRNA corrected 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 kidneys (C) of UUO. In situ hybridization for AT1-R mRNA also showed diminished expression in UUO compared to C kidneys (N = 4). Treatment of UUO rats (N = 4) with Lo increased AT1-R mRNA five times above the levels 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 not vehicle treatment increased RBF (sixfold) and GFR (fivefold) in the UUO kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
Pimentel
J L
JL
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
Wang
S
S
Martinez-Maldonado
M
M
D000208:Acute Disease; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology; D019808:Losartan; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D017706:Lisinopril; D019808:Losartan