Kidney Aminopeptidase A and Hypertension, Part II

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Abstract
Abstract —Aminopeptidase A (APA) is the principal enzyme that metabolizes angiotensin II (Ang II) to angiotensin III. Previously, we showed that kidney APA was elevated in spontaneously hypertensive rats and was reduced after angiotensin-converting enzyme inhibition. In the present study, we sought to determine whether kidney APA expression was altered after chronically elevated Ang II, either exogenously delivered via osmotic minipumps or endogenously produced in two-kidney, one clip (2K1C) hypertensive rats. Ang II (200 ng · kg −1 · min −1 ) was infused subcutaneously for 1 or 2 weeks by osmotic minipumps, and 2K1C rats were tested 4 weeks after unilateral renal artery clipping. Blood pressure was not significantly elevated in the Ang II–infused animals but was significantly increased at 3 and 4 weeks in the 2K1C animals. APA was significantly elevated approximately 2-fold in kidney cortical membranes from Ang II–infused animals but was decreased 45% in the clipped kidney and 18% in the nonclipped kidneys from 2K1C animals. Isolated glomeruli from Ang II–infused animals and the nonclipped kidneys from 2K1C animals had markedly higher APA activity and immunoreactivity. Likewise, histochemical and immunohistochemical studies indicated that APA levels were increased in glomeruli from angiotensin-infused animals and in both nonclipped and clipped kidneys from 2K1C animals. In contrast, tubular APA was decreased in tubular elements from 2K1C animals, most markedly in the clipped kidneys. Thus, despite the increase in glomerular APA expression in kidneys from 2K1C animals, the decrease in tubular APA expression is more extensive and accounts for the measured reduction in total APA in cortical homogenates. Because clipped kidneys are not exposed to high blood pressure, these results suggest that glomerular APA expression is positively regulated and tubular APA negatively regulated by Ang II. These results further suggest that changes in kidney APA expression could influence the progression of angiotensin-dependent hypertension.