RENIN-ANGIOTENSIN SYSTEM IN EXPERIMENTAL DIABETES

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The renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic glomerulopathy. The goal of this project is to explore the relationships and interactions of the systemic and intrarenal renin-angiotensin systems, to define their different regulatory mechanisms, and to determine the site-specific roles of this hormonal system in the modulation of glomerular hemodynamic function in the diabetic kidney. Rationale: (1) Though plasma renin is normal, circulating levels of Angiotensin II (Ang II) are elevated in diabetic rats, indicating discordance of the systemic renin-angiotensin axis (RAS). Origins, mediators, and regulatory consequences of this newly recognized abnormality remain to be explored. (2) Biochemical, molecular biologic, and immunohistochemical studies all indicate heightened activity of the intrarenal RAS, disproportionate to the plasma RAS, as well as redistribution of renal RAS components. More precise localization and quantitation of various RAS components is required to determine their site-specific roles. (3) Though RAS blockade influences renal function, the primary hemodynamic problem (afferent arteriolar vasodilation) must be under the influence of other hormonal systems. General hypothesis: High Ang II levels result from increased activity of non-classical processing pathways, and/or contributions of tissue processing pathways, and may be influenced by interrelated vasodilators. Localized heightened activity of the intrarenal RAS, particularly in the glomeruli and renal vasculature, contributes to local hemodynamic regulation. However, increased RAS activity also provides a stimulus to counter-regulatory vasodilator systems (the kallikrein-kinin system and endothelial derived relaxing factor), which dilate the afferent arteriole and thereby also contribute to the hemodynamic adaptations. Specific aims: (1) To localize the site(s) of altered RAS component processing, by determining whether they result from altered processing pathways, disproportionate contribution of the extrarenal tissue RAS, and/or altered degradation; (2) to determine whether intrarenal Ang II formation and action are increased in the diabetic kidney, and the role of systemic Ang II levels in regulating the intrarenal RAS; (3) to determine whether Ang II stimulates activity of the kallikrein-kinin system and endothelial-derived relaxing factor, and to determine the interrelationships among these vasodilators and the RAS in terms of hemodynamic and hormonal regulation. To achieve these aims, we will use an integrated biochemical, molecular biologic, immunohistochemical, and physiologic approach. Joining these investigative tools together will provide a novel and powerful approach to understanding the pathogenesis of diabetic microangiopathy, potentially allowing more specific and effective prevention of this leading cause of end stage renal disease and morbidity.