This is an application to study the regulation of the ectopeptidase, aminopeptidase-A (APA) and its potential role in the modulation of local renin-angiotensin systems in the kidney and brain. The basis of the study is the hypothesis that APA is a regulated enzyme whose activity is directly or indirectly modified by angiotensins. Furthermore, it is suggested that the activity of APA is enhanced under conditions in which angiotensin levels are elevated and reduced when angiotensin II (Ang II) levels are low. PKC- and tyrosine kinase-dependent phosphorylations are proposed as biochemical substrates responsible for alterations in APA activity. A corollary hypothesis being addressed is the idea that AIII and not AII may be the critical signaling agent in the CNS and that APA plays a paramount role in this necessary conversion. In order to address these hypotheses, the following specific aims will be addressed: 1) Determine the effects of Ang II infusion, angiotensin converting enzyme inhibition, sodium diet, APA inhibitors and AT1 receptor antagonists on renal expression of APA. 2) Determine whether glomerular APA activity is altered in animals with experimental diabetes or hypertension. 3) Determine the effects of inhibition of APA activity on angiotensin metabolism in the CNS. 4) Determine the role of phosphorylation in regulating APA activity. 5) Determine whether mesangial cell APA activity can be regulated by an Ang II receptor-mediated phosphorylation mechanism. 6)Determine the mechanism by which Ang II or other cytokine/serum factors stimulate APA gene expression in mesangial or renal epithelial cells. 7) Determine if cerebrovascular pericytes express Ang II receptors and contract, in response to Ang II.
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