Pathophysiology of Diabetic Nephropathy

描述(由申请人提供)：理由：男性性别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。雌激素和雄激素的相对比例具体影响肾功能障碍和纤维化的机制还没有很好的定义。研究性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；利用与肾脏有关的性激素血管生物学的最新进展；确定新的激素衍生物在男性和女性中可能更安全和没有副作用的用途。性激素的许多细胞作用还没有在肾脏中得到测试，可能会不同地影响肾内离散的间隔(肾小球/血管和肾小管间质)，这些间隔在肾功能丧失中发挥作用。我们将探索经典的和新型的性激素在实验性糖尿病中的作用。为了实现我们的目标，我们将使用补充的生理、生化、分子和免疫组织化学方法，加入体内和体外研究。 假设：(1)与性别相关的对糖尿病肾病的保护作用与内源性雌激素及其代谢产物的保护作用有关；(2)雌激素化合物限制肾素-血管紧张素系统(RAS)的活性，并与阻断RAS的药物协同作用；(3)雌激素化合物改变内皮源性血管活性物质的平衡，使一氧化氮(NO)作用净增加，内皮素-1(ET)减少；(4)性别激素的作用部分与其对血管内皮生长因子(VEGF)的影响及其与纤维化介质的相互作用有关。 具体目的：在实验性糖尿病中，(1)确定性别对糖尿病肾小球和肾小管间质损害的易感性的贡献，以及性别激素的操作是否改变病程；(2)检测性别激素和肾素-血管紧张素系统对血流动力学、血管活性介质和纤维化介质的相互作用；(3)研究性激素和一氧化氮/内皮素系统之间的相互作用，对血流动力学、血管活性介质和纤维化介质的影响；以及(4)确定血管内皮生长因子在改变实验性糖尿病基质形成和降解酶平衡中的作用。

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.