PRR Promotes Obesity Related Hypertension via alpha-ENaC

项目摘要 高血压是肥胖的直接后果，并且其患病率随着年龄的增长而迅速增加。 日益增长的肥胖症流行。高血压还显著地导致当今世界的发病率和死亡率。 社会，同时增加医疗保健支出。然而，我们对这些疾病的病理生理变化的了解， 促进高血压的肥胖仍然是不完全的。更好地理解这些过程对于 制定新的治疗策略。 肥胖相关的高血压在很大程度上是由于增加钠潴留，这反过来又发生 通过改变肾单位中钠通道的表达和活性。ENaC就是这样一个重要的 在远曲小管和集合管中的通道。虽然一些调解人，如增加 血管紧张素II（Ang II）、盐皮质激素活性和炎性细胞因子与 增加ENaC活性在肥胖的背景下，我们认为可能涉及其他因素。的 （原）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， 其表达因炎症而增加。虽然最初被提议作为肾素的一种成分- AGN-ALDOSTERONE SYSTEM（RAAS）是一种增加肾素和前肾素活性的系统，PRR现在被认为 具有RAAS独立的细胞内信号传导特性。这包括PI 3 K/Akt/mTOR的激活。 通路我们实验室和其他实验室最近的工作已经证明了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，不为人知的是， 这种关系是否在肥胖相关的高血压中起重要作用。 因此，该项目的中心假设是，在肥胖症中，肾PRR增加上调α- ENaC的表达和活性，导致钠潴留和促进高血压。两个具体目标是 提出了目的1将使用一种新的方法来测试PRR是否通过肥胖期间的α-ENaC诱导高血压。 可诱导肾单位特异性PRR敲除小鼠。目的2将在小鼠内髓集合管细胞中进行试验 肥胖症中存在的炎性细胞因子是否增加PRR表达，导致肥胖症中PRR表达增加， ENaC活性通过PI 3 K/Akt/mTOR/血清和糖皮质激素诱导的激酶亚型1（SGK-1）信号传导 通路 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技术。 预防和治疗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.