PRR Promotes Obesity Related Hypertension via alpha-ENaC

项目摘要 高血压是肥胖的直接后果，其患病率随着 日益严重的肥胖症流行。高血压也是当今世界发病率和死亡率的重要原因。 同时增加医疗保健支出。然而，我们对脑血管疾病病理生理变化的了解 促进高血压的肥胖仍然是不完整的。更好地理解这些过程对于 设计新的治疗策略。 肥胖相关的高血压在很大程度上是由于钠滞留增加而导致的。 通过改变肾单位钠通道的表达和活性。ENAC就是这样一个重要的 在远端曲管和集合管中的通道。而几个调解人，如增加了 血管紧张素II(Ang II)、盐皮质激素活性和炎性细胞因子被认为与 在肥胖的背景下，ENaC活性增加，我们认为可能涉及其他因素。这个 (Pro)肾素受体(PRR)是一种在多个肾脏结构中表达的蛋白质，包括远端肾单位和 它的表达因炎症而增加。尽管最初被提议作为肾素的一个组成部分- 血管紧张素-醛固酮系统(RAAS)可增加肾素和前肾素的活性，现已知PRR 具有RAAS独立的细胞内信号特性。这包括激活PI3K/Akt/mTOR 路径。我们实验室和其他实验室最近的工作证明了PRR的Ang II独立能力 在正常和低盐条件下上调α-ENaC亚基。然而，尚不清楚的是， 这种关系是否在肥胖相关高血压中起着重要作用。 因此，该项目的中心假设是，在肥胖症患者中，肾脏PRR增加会上调α- ENAC的表达和活性，导致钠离子滞留，促进高血压。两个具体目标是 建议。目标1将测试在肥胖期间PRR是否通过α-ENaC诱导高血压 可诱导的肾单位特异性PRR基因敲除小鼠。AIM 2将在小鼠内髓集合管细胞中进行测试 肥胖中存在的炎性细胞因子是否会增加PRR的表达，从而导致 通过PI3K/Akt/mTor/血清和糖皮质激素诱导的蛋白同工酶1(SGK-1)信号通路激活ENAC 路径。 从拟议的研究中获得的知识可能有助于开发令人兴奋的新的 防治肥胖性高血压的治疗策略。

Project Summary Hypertension is a direct consequence of obesity and one whose prevalence is increasing rapidly with the growing obesity epidemic. Hypertension also contributes significantly to morbidity and mortality in today’s society while increasing healthcare expenditures. However, our knowledge of the pathophysiologic changes in obesity which promote hypertension remains incomplete. Better understanding these processes is crucial to devising new treatment strategies. Obesity related hypertension is in large part due to increased sodium retention which in turn occurs through changes in expression and activity of sodium channels in the nephron. ENaC is one such important channel in the distal convoluted tubules and collecting ducts. While several mediators such as increased angiotensin II (Ang II), mineralocorticoid activity, and inflammatory cytokines have been implicated in increasing ENaC activity in the setting of obesity, we believe that additional factors may be involved. The (pro)renin receptor (PRR) is a protein expressed in multiple kidney structures including the distal nephron and whose expression is increased by inflammation. Although initially proposed as a component of the renin- agniotensin-aldosterone system (RAAS) that increases activity of renin and prorenin, PRR is now known to have RAAS independent intracellular signaling properties. This includes activation of the PI3K/Akt/mTOR pathway. Recent work by our laboratory and others have demonstrated an Ang II independent ability of PRR to upregulate the α-ENaC subunit under normal and low salt conditions. What is not known, however, is whether this relationship plays a significant role in obesity related hypertension. The central hypothesis of this project is therefore that, in obesity, increased renal PRR upregulates α- ENaC expression and activity, leading to sodium retention and promoting hypertension. Two specific aims are proposed. Aim 1 will test whether PRR induces hypertension through α-ENaC during obesity using an inducible nephron specific PRR knockout mouse. Aim 2 will test in mouse inner medullary collecting duct cells whether inflammatory cytokines that are present in obesity increase PRR expression, leading to increased ENaC activity via the PI3K/Akt/mTOR/serum and glucocorticoid-inducible kinase isoform 1 (SGK-1) signaling pathway. The knowledge gained from the proposed studies could potentially help develop exciting new therapeutic strategies for prevention and treatment of obesity induced hypertension.