Gender and susceptibility to kidney damage in high BP

描述（由申请人提供）：雄激素补充剂的使用在美国越来越普遍，主要是在患有慢性心血管疾病（如高血压和II型糖尿病）的中老年男性普通人群中，他们接受睾酮补充剂治疗骨质疏松症，改善性欲和幸福感，并改善性表现。尽管雄激素的普遍使用，雄激素补充剂在健康个体中的长期影响，更不用说在患有慢性心血管-肾脏疾病（CV-RD）的个体中的长期影响，是未知的。我们实验室和其他实验室的最新研究表明，内源性雄激素导致血压正常和高血压雄性大鼠的肾损伤更大。然而，关于雄激素补充剂是否会加重肾损伤以及通过何种机制加重肾损伤的信息很少。本提案中待检验的总体假设是，雄激素补充剂通过NADPH氧化酶直接增加氧化应激，并通过增加向肾小球的压力传递而在血流动力学上加重肾损伤。我们进一步假设雄激素补充剂通过刺激RAS间接增加ROS。最后，将检验雄激素补充剂可以激活肾脏中的NF-DB促进炎症的假设。在人类中，肾损伤的两个主要原因是高血压和II型糖尿病。因此，将在雄性大鼠模型中进行研究，这些模型模拟患有CV-RD并处方雄激素补充剂的男性：患有高血压肾损伤的男性（高盐饮食下肾脏质量减少的大鼠）和患有II型糖尿病的男性（Zucker大鼠），使用睾酮，这是男性最常见的处方雄激素。还将在人类男性系膜细胞中进行研究。该提案的具体目的是验证以下假设：1）雄激素补充剂会加重高血压或II型糖尿病大鼠的肾损伤; 2）雄激素补充剂会通过增加NADPH氧化酶介导的氧化应激而加重肾损伤，肾内RAS在介导雄激素补充剂诱导的氧化应激中起作用; 3）雄激素补充剂将通过激活NF-DB而加剧肾损伤，导致炎性细胞因子增加; 4）雄激素补充剂将通过增加向肾小球的压力传递而加剧肾损伤。

DESCRIPTION (provided by applicant): The use of androgen supplements is becoming increasingly prevalent in the United States mainly in the general population of middle-aged and elderly men with chronic cardiovascular diseases, such as hypertension and type II diabetes, who receive testosterone supplements to treat osteoporosis, improve libido and feelings of well-being, and to improve sexual performance. Despite the common use of androgens, the long term impact of androgen supplements in healthy individuals, much less in individuals who suffer from chronic cardiovascular-renal diseases (CV-RD), is unknown. Recent studies from our laboratory and others indicate that endogenous androgens contribute to greater renal injury in normotensive and hypertensive male rats. However, there is little information regarding whether androgen supplements exacerbate renal injury and by what mechanisms. The overall hypothesis to be tested in this proposal is that androgen supplements exacerbate renal injury by directly increasing oxidative stress via NADPH oxidase, and hemodynamically by increasing transmission of pressure to the glomerulus. We further hypothesize that androgen supplements indirectly increase ROS by stimulating the RAS. Finally, the hypothesis will be tested that androgen supplements could activate NF-DB in the kidney promoting inflammation. In humans the two leading causes for renal injury are hypertension and type II diabetes. Therefore, studies will be performed in male rat models that mimic men who suffer from CV-RD and are prescribed androgen supplements: men with hypertensive renal injury (rats with reduced renal mass on high salt diet), and men with type II diabetes (Zucker rats), using testosterone, the most commonly prescribed androgen for men. Studies will also be performed in human male mesangial cells. The specific aims of the proposal are to test the hypotheses that: 1) androgen supplements will exacerbate renal injury in rats with hypertension or type II diabetes; 2) androgen supplements will exacerbate renal injury by increasing oxidative stress mediated by NADPH oxidase and that the intrarenal RAS plays a role in mediating androgen supplement-induced oxidative stress; 3) androgen supplements will exacerbate renal injury by activating NF-DB leading to increased inflammatory cytokines; 4) androgen supplements will exacerbate renal injury by increasing transmission of pressure to the glomerulus.