The objectives of this proposal are to determine the pathways for the intra-renal production of the bioactive peptide angiotensin-(1-7) [Ang-(1-7)] and the physiologic role of the peptide in renal function. This endogenous peptide elicits potent diuretic and natriuretic effects in the kidney. Low concentrations of Ang-(1-7) inhibit sodium transport in the isolated proximal tubules. In marked contrast to the potent hemodynamic and antinatriuretic actions of Ang II, Ang-(1-7) does not reduce renal blood flow, alter GFR or stimulate aldosterone release. Preliminary findings of the principal investigator indicate significant excretion of Ang-(1-7) by the kidney, converting enzyme inhibition (which attenuates renal damage) augments the renal excretion of Ang-(1-7), and neprilysin (endopeptidase 24.11) inhibition reduces the excretion of Ang-(1-7), but augments Ang I and Ang II. These studies propose that Ang-(1-7) is one of the predominant Ang peptides produced in the kidney and that this intrarenal hormone contributes to basal renal function by opposing the actions of Ang II.
The aims of the proposal will: 1) establish the intrarenal site of synthesis and release using immunocytochemical and biochemical methods; 2) determine the enzymatic pathways involved in the generation and degradation of Ang-(1-7) in discrete areas of the kidney; 3) identify and characterize binding sites in the kidney which mediate the actions of Ang-(1-7) by in vitro autoradiographic and membrane binding methods; and 4) define the renal actions of the peptide by the functional blockade of intrarenal Ang-(1-7) with the Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7) or a selective monoclonal antibody. The proposed studies are a direct extension of ongoing research to understand the significance of differential processing of angiotensin peptides. These studies will establish the basic processing pathways and the renal actions of Ang-(1-7). The knowledge gained from the proposed experiments should directly enhance our understanding of the physiologic role of Ang-(1-7) in the kidney, as well as reveal the interactions between Ang-(1-7) and Ang II in cardiovascular regulation. From this foundation, his long-term goals will determine whether pathophysiological changes in intrarenal Ang-(1-7) contribute to different models of hypertension or renal failure.
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