Several non-cyclooxygenase arachidonic acid (AA) metabolites have taken on special significance as potential regulators of vasomotion, transport and renin secretion. One of them, 12(S)-HETE, a product of glomerular and vascular lipoxygenase, is the subject of this proposal. The tubular mechanism controlling 12-HETE production and the effector responses to it, particularly renin secretion and renal hemodynamics, will be studied in the rat-isolated kidney. This experimental preparation is an ideal model to measure and manipulate selectively the components of the renal lipoxygenase system in terms of: 1) its response to vasoactive peptides and perfusate compositional changes; 2) interactions with other AA-metabolizing enzymes: cyclooxygenases and cytochrome P450-monooxygenases, and 3) effects on renin secretion, GFR, renovascular resistance and salt and water excretion. Changes in renal lipoxygenase activity (measured by RIA of 12-HETE) and associated renal functional changes will be produced by either amplifying or suppressing a postulated tubular signal originating in the thick ascending limb/macula densa. A reciprocal relationship will be sought between renal cyclooxygenase and lipoxygenase activities as they relate to 1) control of renin secretion and 2) renovacular responsiveness to angiotensin II and AVP. Studies on isolated glomeruli will permit more rigorous control of peptide interactions with AA metabolizing enzymes as they relate to renin secretion. We will examine the feasibility of translating some of our findings to conscious animals as an integral part of this proposal. Finally, in rats made diabetic with streptozotocin, alterations in renin secretion and blunted renovascular response to AVP and angiotensin II will be examined in terms of abnormalities in renal lipoxygenase activity.
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