The tissue kallikrein-kinin system has been implicated in the regulation of renal function, blood flow (BF) and blood pressure (BP) and in the pathogenesis of hypertension. We have provided evidence that kinins act mainly as local hormones (autacoids) in the regulation of renal function and in the acute renal hemodynamic, natriuretic and diuretic effects of angiotensin-converting enzyme inhibitors (ACE). Here we propose to test the general hypothesis that endogenous kinins regulate renal function (GFR, total and papillary BF) via EDRF and eicosanoids, and that they act in synergism with ANF to regulate water and sodium excretion, especially in situations involving high renal kinins and/or ANF of endogenous origin. By these mechanisms, kinins play a role in the chronic regulation of renal function, acting as both natriuretic and diuretic hormones. Specifically, we propose: I) to determine a) whether kinins in the kidney act on B1 and/or B2 receptors; b) whether endogenous kinins act on receptors on the basolateral and/or luminal sides of the nephron; and c) to identify the site of expression of the B2 kinin receptor in the microdissected nephron; II) to determine in vivo whether the effects of endogenous kinins on renal function are mediated in part by EDRF and PGs, and whether part of their effects are antagonized by EDCFs (PG-endoperoxide and thromboxane, TxA2). III) to further advance the hypothesis that kinins and ANF act synergistically. Their effects on sodium flux will be tested in isolated perfused cortical collecting ducts. We have evidence that kinins act synergistically with ANF, inhibiting ISC and PD on cortical collecting cells in culture. We propose to study the mechanism(s) by which kinins and ANF act synergistically to decrease transport; IV) to study in vivo whether there is an interaction between kinins and ANF of endogenous origin. For this, we will determine the effect of blocking kinins and/or ANF (monoclonal antibodies) on: a) water and sodium excretion, b) renal cortical and papillary BF, and c) renal interstitial pressure. We will study situations in which endogenous ANF release is stimulated, such as volume expansion in normal and DOCA-salt rats; and V) to determine whether chronic blockade of kinin receptors alters renal function (GFR, renal BF, proteinuria and water and sodium excretion) in rats fed high protein diets and in rats with nephrotic syndrome treated with kininase inhibitors.
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