Contribution of Renal Tubule Insulin Receptor on Proximal Tubule Sodium Transport and Hypertension int he Metabolic Syndrome

项目摘要/摘要 代谢综合征患者的高血压导致巨大的经济、社会和医疗成本 美国。尽管有几条证据表明高血压在代谢综合征中有明显的 由特发性(原发性)高血压引起，这一原因尚不清楚，患者接受经验性治疗。 在过去的30年里，许多实验室的贡献支持了这样一种假设，即增强胰岛素 肾脏中的信号在本病的发病机制中起着关键作用。申请人的初步数据 证实了肾脏中的胰岛素作用导致高血压的假设。 代谢综合征，提示近端肾小管钠转运增加，扩张血液 体量和血压升高。申请人具有(1)特征：一种用于研究 肾脏、血压和代谢综合征的交集和(2)产生了一种新的可诱导小管 胰岛素受体基因敲除小鼠研究胰岛素受体信号对钠转运和 血压。除了申请者的贡献外，指导和科学环境使他 一个理想的候选人发展独立性的肾脏生理学研究解决这一重要问题。 在这里，申请人提出了三个目的来研究胰岛素受体信号在代谢中的作用 急性压力性钠尿症综合征(AIM 1)，近端小管钠转运蛋白活性调节 对急性和慢性高血压的反应(目标2)，以及对近端小管上皮细胞模式的反应 由胰岛素受体信号、代谢综合征或两者同时产生的转录组(目标3)。成功 这些目标的完成将开始弥合胰岛素在整个动物中的作用之间的认识差距 个体细胞中的生理和转运蛋白的活动和调节。另外，通过这次培训， 机制申请人将学会成功地进行基础科学独立研究的技能 肾脏学。

Project Summary / Abstract Hypertension in patients with Metabolic Syndrome incurs a large financial, societal, and health cost in the United States. Despite several lines of evidence that hypertension in the Metabolic Syndrome has a distinct cause from idiopathic (essential) hypertension, this cause is not known and patients are treated empirically. Contributions from many labs over the last 30 years have supported the hypothesis that enhanced insulin signaling in the kidney plays a critical role in the pathogenesis of this disease. The Applicant's preliminary data confirms the hypothesis that insulin action in the kidney contributes to hypertension in a mouse model of Metabolic Syndrome and suggests that proximal tubular sodium transport may be increased, expanding blood volume, and increasing blood pressure. The Applicant has (1) characterized: a mouse model to study the intersection of the kidney, blood pressure, and Metabolic Syndrome and (2) generated a novel inducible tubule insulin receptor knockout mouse to study the contribution of insulin receptor signaling to sodium transport and blood pressure. In addition to the Applicant's contributions, the mentoring and scientific environment make him an ideal candidate to develop independence in renal physiology research addressing this important question. Here, the Applicant proposes three aims to study the contribution of insulin receptor signaling in the Metabolic Syndrome to acute pressure natriuresis (Aim 1), to regulators of proximal tubule sodium transporter activity in response to acute and chronic hypertension (Aim 2), and to patterns within the proximal tubule epithelial cell transcriptome generated by insulin receptor signaling, the Metabolic Syndrome, or both (Aim 3). Successful completion of these aims will begin to bridge the gap in knowledge between the role of insulin in whole animal physiology and transporter activity and regulation in individual cells. In addition, through this training mechanism the Applicant will learn the skills to successfully conduct independent research in basic science nephrology.