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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National Heart, Lung, and Blood Institute (NHLBI)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Mount Sinai School of Medicine
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New York
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Troyanovskaya, M; Jayaraman, G; Song, L et al. (2000) Aminopeptidase-A. I. CDNA cloning and expression and localization in rat tissues. Am J Physiol Regul Integr Comp Physiol 278:R413-24
Jiang, Q; Troyanovskaya, M; Jayaraman, G et al. (2000) Aminopeptidase-A. II. Genomic cloning and characterization of the rat promoter. Am J Physiol Regul Integr Comp Physiol 278:R425-34
Song, L; Healy, D P (1999) Kidney aminopeptidase A and hypertension, part II: effects of angiotensin II. Hypertension 33:746-52
Healy, D P; Song, L (1999) Kidney aminopeptidase A and hypertension, part I: spontaneously hypertensive rats. Hypertension 33:740-5
Song, L; Wilk, S; Healy, D P (1997) Aminopeptidase A antiserum inhibits intracerebroventricular angiotensin II-induced dipsogenic and pressor responses. Brain Res 744:1-6
Troyanovskaya, M; Song, L; Jayaraman, G et al. (1996) Expression of aminopeptidase A, an angiotensinase, in glomerular mesangial cells. Hypertension 27:518-22
Healy, D P; Ye, M Q; Troyanovskaya, M (1995) Localization of angiotensin II type 1 receptor subtype mRNA in rat kidney. Am J Physiol 268:F220-6
Song, L; Ye, M; Troyanovskaya, M et al. (1994) Rat kidney glutamyl aminopeptidase (aminopeptidase A): molecular identity and cellular localization. Am J Physiol 267:F546-57
Song, L; Wilk, E; Wilk, S et al. (1993) Localization of immunoreactive glutamyl aminopeptidase in rat brain. I. Association with cerebral microvessels. Brain Res 606:286-94
Healy, D P; Wilk, S (1993) Localization of immunoreactive glutamyl aminopeptidase in rat brain. II. Distribution and correlation with angiotensin II. Brain Res 606:295-303

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