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

项目概要/摘要 代谢综合征患者的高血压在美国引起了巨大的经济、社会和健康成本。 美国的尽管有一些证据表明代谢综合征中的高血压具有明显的 由于原发性高血压的原因，这种原因尚不清楚，患者只能凭经验治疗。 在过去的30年里，许多实验室的贡献都支持了这样一个假设，即增强胰岛素 肾脏中的信号传导在这种疾病的发病机制中起关键作用。申请人的初步资料 证实了这一假设，即胰岛素作用在肾脏有助于高血压的小鼠模型， 代谢综合征，并表明近端肾小管钠转运可能增加，扩大血液 量和增加血压。申请人已经（1）表征了： 肾脏，血压和代谢综合征的交叉点，（2）产生了一种新的诱导小管 胰岛素受体敲除小鼠研究胰岛素受体信号传导对钠转运的贡献， 血压.除了申请人的贡献，导师和科学环境使他 一个理想的候选人，以发展独立的肾脏生理学研究解决这一重要问题。 在此，申请人提出了三个目的来研究胰岛素受体信号传导在代谢调节中的贡献。 急性压力性尿钠排泄综合征（Aim 1），近端小管钠转运蛋白活性调节剂， 对急性和慢性高血压的反应（目的2），以及对近端小管上皮细胞内模式的反应 由胰岛素受体信号传导产生的转录组、代谢综合征或两者（目的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知识差距， 生理学和转运蛋白活性以及个体细胞中的调节。此外，通过此次培训， 机制，申请人将学习成功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.