Pathophysiology of Diabetic Nephropathy

描述（由申请人提供）：理由：男性是糖尿病肾病进展的重要危险因素，糖尿病肾病是终末期肾病的主要原因。雌激素与雄激素的相对比例特异性影响肾功能障碍和纤维化的机制尚不明确。研究性别激素有很强的理论基础：了解雌激素保护和/或雄激素损害肾脏的机制；利用性别激素血管生物学的最新进展，因为它们与肾脏有关；并确定对男性和女性更安全，无副作用的新型激素衍生物的效用。性类固醇的许多细胞作用尚未在肾脏中进行测试，并且可能不同地影响在肾功能丧失中起作用的离散肾内室（肾小球/血管与小管间质）。我们将探讨经典和新型性别激素在实验性糖尿病中的作用。为了实现我们的目标，我们将使用互补的生理、生化、分子和免疫组织化学方法，加入体内和体外研究。

DESCRIPTION (provided by applicant): Rationale: Male gender is an important risk factor for progression of diabetic nephropathy, the leading cause of end-stage renal disease. Mechanisms by which the relative ratio of estrogen to androgen specifically impacts renal dysfunction and fibrosis are not well defined. There is strong rationale to study gender hormones: to understand the mechanisms by which estrogens protect, and/or androgens injure, the kidney; to utilize recent advances in the vascular biology of gender hormones, as they pertain to the kidney; and to determine the utility of new hormonal derivatives which may be safer and free of side effects, in both men and women. Many cellular actions of sex steroids have not been tested in the kidney, and are likely to differentially affect the discrete intrarenal compartments (glomerular/vascular vs. tubulointerstitial) which play a role in loss of renal function. We will explore the role of classical and novel gender hormones in experimental diabetes. To achieve our aims, we will use complementary physiological, biochemical, molecular, and immunohistochemical approaches, joining in vivo and in vitro studies. Hypotheses: (1) Gender-related protection against diabetic nephropathy is related to the protective effect of endogenous estrogen and its metabolites; (2) estrogenic compounds limit the activity of the renin-angiotensin system (RAS), and act synergistically with drugs which block the RAS; (3) estrogenic compounds shift the balance in endothelial-derived vasoactive mediators, with a net increase in nitric oxide (NO) action, and reduction in endothelin-1 (ET); and (4) actions of gender hormones relate in part relate to their effects on vascular endothelial growth factor (VEGF), and its interactions with fibrotic mediators. Specific Aims: In experimental diabetes, (1) to determine the contribution of gender to susceptibility to diabetic glomerular and tubulointerstitial injury, and whether manipulation of gender hormones alters the course of disease; (2) to examine the interactions among gender hormones and the renin-angiotensin system on hemodynamics, vasoactive mediators, and fibrosis mediators; (3) to examine the interactions among gender hormones and the nitric oxide/endothelin systems, on hemodynamics, vasoactive mediators, and fibrosis mediators; and (4) to determine the role of VEGF in altering the balance of matrix forming and degrading enzymes in experimental diabetes.