Glomerular hemodynamic changes and angiotensin II (Ang II) participate in the age-related changes in renal function. Aging rats develop glomerular capillary hypertension, and blockade of Ang 11 slows age-related nephropathy. However, renal responsiveness to Ang 11 blockade declines in the course of aging. Three complementary hypotheses are proposed: First, the renal renin-angiotensin system (RAS) may be considered as two distinct systems: a vascular system (composing the plasma and vasculature, including glomeruli), and a tubulointerstitial system. Second, these two systems change with aging, not necessarily in coordinated fashion with maladaptive RAS changes contributing to age-related injury. Third, in aging there is a shift in the balance between constrictor and vasodilatory mediators, so that the former predominate. In support of these hypotheses, the applicant has found that plasma Ang II levels fall, but that renal Ang II levels (presumably tubulointerstitial) are high in the aging rat. Furthermore, aging rats exhibit greater renal responses to vasoconstrictors, but not to vasodilator stimuli. Thus, a predominance of Ang II (and other vasoconstrictors) may be a heretofore unrecognized key participant in the pathogenesis of age-related renal injury. Perturbations in the balance affect hemodynamics, but also lead to changes in effectors which are regulated by those mediators. There are three specific aims. (1) To localize and quantify the anomalies of the vascular and tubulointerstitial renin angiotensin systems in aging, by determining the site(s) of discordant RAS component processing; (2) to evaluate the mechanisms by which long-term angiotensin converting enzyme (ACE) inhibition protects against chronic age-related injury, by comparison with other antihypertensive regimens, and by evaluating effects of therapy on hemodynamic function and mediators of injury; and (3) to examine the activity of the renal dopaminergic system, and its interactions with the RAS, in regulation of hemodynamic and natriuretic function in the aging kidney. The use of a combined physiological, biochemical, immunohistochemical, and molecular biologic approach should gain insight into this clinically important but understudied problem.
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