Epoxyeicosanoids and Renal Vascular Function in Obesity & Hypertension

描述（由申请人提供）：世界卫生组织最近将肥胖列为全球最严重的健康问题之一。慢性肾脏疾病增加的主要原因之一是肥胖相关的2型糖尿病及其与高血压共存的增加。炎症、内皮功能障碍和胰岛素抵抗等心血管危险因素的聚集在肥胖和高血压中是相互交织的。这三种危险因素在很大程度上导致了慢性肾脏疾病在肥胖和高血压中的进展，也就是现在所说的心脏代谢综合征。TNF-是脂肪组织分泌的重要细胞因子，可增加肥胖患者心血管风险和终末器官损伤。我们最近证明TNF-可以降低Cyp2c衍生的环氧二碳三烯酸（EETs）。这些Cyp2c衍生的环氧二十烷类化合物具有肾脏和心血管保护特性。一个可能将TNF-和环氧化物与内皮功能障碍和肾损伤联系起来的信号通路是NFB激活细胞粘附分子如MCP-1。TNF-、环氧二十烷酸和NFB在肥胖和高血压慢性肾病进展中的作用尚未阐明。因此，我们将验证TNF-升高、环氧化物降低和MCP-1升高导致肥胖和高血压患者肾血管损伤的假设。我们将研究高脂饮食对高血压动物传入小动脉功能、血压和肾损伤的影响。目前的提案将确定TNF-， EETs， NFB和MCP-1在肥胖和高血压中的作用以及这些途径之间的相互作用。该建议结合了新的代谢氧脂质谱分析，RT-PCR阵列和细胞机制的靶向分析，将允许对肥胖和高血压肾病进展机制的独特见解。总的来说，本应用程序中提出的实验将为肥胖和高血压慢性肾脏疾病的进展提供新的机制见解。

DESCRIPTION (provided by applicant): The World Health Organization has recently labeled obesity as one of the top global health problems. One of the primary reasons for the increase in chronic kidney disease is the increase in obesity related type 2 diabetes and its co-existence with hypertension. The clustering of cardiovascular risk factors such as inflammation, endothelial dysfunction and insulin resistance are intertwined in obesity and hypertension. This triad of risk factors is largely responsible for the progression of chronic kidney disease in obesity and hypertension or what is now known as Cardiometabolic Syndrome. TNF- is an important cytokine secreted by adipose tissue that can increase cardiovascular risk and end organ damage in obesity. We have recently demonstrated that TNF- can decrease Cyp2c derived epoxyeicosatrienoic acids (EETs). These Cyp2c derived epoxyeicosanoids have renal and cardiovascular protective properties. A signaling pathway that could possible link TNF- and epoxides to endothelial dysfunction and renal damage is NFB activation of cell adhesion molecules such as MCP-1. The contribution of TNF-, epoxyeicosanoids, and NFB to the progression of chronic kidney disease in obesity and hypertension has not been elucidated. Therefore, we will test the hypothesis that increased TNF- , decreased epoxides and increased MCP-1 contribute to renal vascular injury in obesity and hypertension. We will determine the effects of high fat diet induced obesity on afferent arteriolar function, blood pressure and renal injury in hypertensive animals. The current proposal will define the contribution of TNF-, EETs, NFB and MCP-1 and interactions between these pathways in obesity and hypertension. This proposal incorporates novel metabolic oxylipid profiling, RT-PCR arrays and targeted analysis of cellular mechanisms that will allow for unique insight concerning mechanisms that contribute to the progression of kidney disease in obesity and hypertension. Collectively, the proposed experiments in this application will provide novel mechanistic insight on the progression of chronic kidney disease in obesity and hypertension. Project Narrative: The World Health Organization has recently labeled obesity as one of the top global health issues. One of the primary reasons for the increase in chronic kidney disease is the increase in obesity related diabetes and its co- existence with hypertension. This project will test the hypothesis that interactions between fatty acid metabolites and inflammatory molecules accelerate the progression of chronic kidney disease in obesity and hypertension. On the whole, the proposed experiments in this application will provide novel insight and therapeutic targets for the treatment of chronic kidney disease in obesity and hypertension.