RENAL ANGIOTENSIN-CONVERTING ENZYME PROMOTES RENAL DAMAGE DURING URETERAL OBSTRUCTION

Purpose: We and others have shown that angiotensin II has a pivotal ro le in renal damage in various renal injuries. Although most angiotensi n II actions are associated with the angiotensin type 1 receptor, ther e is increasing evidence that the angiotensin type 2 receptor also tra nsduces some important effects of angiotensin II. In this regard we re cently observed that mice with genetically engineered disruption of th e angiotensin type 2 receptor, termed Agtr2 mutants, are more suscepti ble to structural renal damage after ureteral obstruction. Recent evid ence suggests that a genetically determined increase in angiotensin co nverting enzyme activity in humans promotes end organ damage. Therefor e, we determined whether renal damage in Agtr2 mutants is associated w ith heightened angiotensin converting enzyme activity. Materials and M ethods: We studied 28 wild type and 19 Agtr2 mutant mice with unilater al ureteral obstruction. Seven days after obstruction was created seru m samples were obtained to evaluate angiotensin converting enzyme acti vity. The obstructed and contralateral kidneys were harvested for hist ological analysis and determination of renal angiotensin converting en zyme activity by high pressure liquid chromatography. Results: Renal a ngiotensin converting enzyme was uniformly higher than serum angiotens in converting enzyme in normal wild type and Agtr2 mutant mice. Howeve r, even at baseline Agtr2 mutant mice had strikingly higher renal angi otensin converting enzyme activity than normal wild type mice (mean pl us or minus standard error 1,492 +/- 83 versus 450 +/- 60 milliunits p er gm. tissue weight, p <0.0005). Histological analysis revealed more extensive parenchymal damage in the obstructed kidneys of mutant mice than in identically treated controls. Notably while unilateral uretera l obstruction decreased renal angiotensin converting enzyme activity i n each group, activity remained persistently higher in the Agtr2 mutan ts than in normal mice (mean 742 +/- 146 versus 310 +/- 43 milliunits per gm. tissue weight, p <0.005). Conclusions: We propose that elevate d renal angiotensin converting enzyme activity contributes to more sev ere renal parenchymal damage in ureteral obstruction by promoting the availability of growth factors, such as angiotensin II, or depleting a ntiproliferation factors, such as bradykinin or nitric oxide. These fi ndings complement previous observations that angiotensin converting en zyme inhibition preserves the renal parenchyma after injury, including obstruction.