UP-REGULATION OF ANGIOTENSIN-II TYPE-1 RECEPTOR GENE-EXPRESSION IN CHRONIC RENOVASCULAR HYPERTENSION

Although the renin-angiotensin system has been implicated in the pathogenesis of renovascular hypertension (RVH), blood pressure does not parallel serum levels of renin or angiotensin II (AII) in chronic RVH. Upregulation of angiotensin II type 1 receptor (AT(1)) gene expression may explain this paradox and clarify the pathogenesis of chronic hypertension in RVH. To investigate this hypothesis, we studied changes in AT(1) mRNA levels in rat kidney in a two-kidney, one-clip (2K1C) rat model of RVH, Animals were sacrificed at 1 or 10 weeks postoperatively, Blood pressure was measured with a tail cuff photosensor, Relative gene expression was quantitated by dot blotting total RNA, hybridizing with a cDNA probe for AT(1), and quantitating signal intensity with scanning densitometry, A significant increase in blood pressure (BP) was observed at 1 week postoperatively (Delta BP: 2K1C = +24 mm Hg, n = 3; controls = +7 mm Hg, n = 3; P < 0.05), and at this time relative AT(1) mRNA levels actually decreased in the clipped kidney (P < 0.05). Hypertension intensified 10 weeks postoperatively (Delta BP: 2K1C = +46 mm Hg, n = 20; controls = -17 mm Hg, n = 7; P < 0.005) and, remarkably, was paralleled by an almost sevenfold upregulation of AT(1) mRNA levels in the clipped kidney (P < 0.005) and more than eightfold in the unclipped kidney (P < 0.005) of 2K1C animals, Upregulation of renal AT(1) gene expression could lead to increased AT(1) receptor production, hypersensitivity to AII, and chronic hypertension in RVH. (C) 1995 Academic Press, Inc.