Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloo n-injured carotid arteries and induces marked vascular and tubulointerstiti al injury in kidneys. We examined how the AT1 receptor is modulated and whe ther blockade of the receptor with losartan could prevent the phenotypic an d cellular changes, We also examined the role of the local renin-angiotensi n system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and med ial thickening in balloon-injured carotid arteries. Renal injury was manife sted by proteinuria, glomerular phenotypic changes (mesangial expression of alpha -actin and podocyte expression of desmin), and tubulointerstitial in jury with the tubular upregulation of the macrophage-adhesive protein, oste opontin, the interstitial accumulation of macrophages and myofibroblasts, a nd the deposition of collagen types III and IV. Ang II infusion decreased A T1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and inju ry to both carotid and kidney. Ang II infusion was also associated with an in crease in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies de monstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activat ion, the injury appears to be mediated solely by the exogenous Ang II. Copy right (C) 2001 S. Karger AG, Basel.