Pathophysiology of Diabetic Nephropathy

糖尿病肾病的病理生理学

• 批准号: 6678595
• 负责人: SHARON ANDERSON
• 金额: $ 24.44万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678595
• 关键词: androgens; diabetic nephropathy; disease /disorder proneness /risk; endothelin; enzyme activity; estradiol; estrogens; fibrosis; gender difference; hemodynamics; hormone metabolism; hormone regulation /control mechanism; immunocytochemistry; intermolecular interaction; kidney pharmacology; laboratory rat; morphometry; nitric oxide; pathologic process; prostaglandin endoperoxide synthase; renin angiotensin system; sex hormones; tissue /cell culture; vascular endothelial growth factors; vasoactive agent; western blottings

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.

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具体影响肾功能障碍和纤维化的机制尚不清楚。研究性别激素有充分的理由：了解雌激素保护和/或雄激素损伤肾脏的机制；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；并确定新的激素衍生物的效用，这种衍生物对男性和女性来说可能更安全且无副作用。性类固醇的许多细胞作用尚未在肾脏中进行测试，并且可能对离散的肾内隔室（肾小球/血管与肾小管间质）产生不同的影响，这些隔室在肾功能丧失中发挥作用。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学、生化、分子和免疫组织化学方法，结合体内和体外研究。 假设：（1）性别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介质的平衡，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。 具体目标：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伤易感性的影响，以及控制性别激素是否会改变病程； (2)考察性别激素与肾素-血管紧张素系统对血流动力学、血管活性介质、纤维化介质的相互作用； (3) 检查性别激素和一氧化氮/内皮素系统之间对血流动力学、血管活性介质和纤维化介质的相互作用； (4) 确定 VEGF 在改变实验性糖尿病基质形成和降解酶平衡中的作用。