Epoxyeicosanoids and Renal Vascular Function in Obesity & Hypertension

描述(申请人提供)：世界卫生组织最近将肥胖列为全球最大的健康问题之一。慢性肾脏疾病增加的主要原因之一是肥胖相关的2型糖尿病的增加及其与高血压的共存。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与肥胖和高血压相互交织。这三种危险因素在很大程度上导致了肥胖和高血压的慢性肾脏疾病的发展，也就是现在所知的心脏代谢综合征。肿瘤坏死因子-α是一种由脂肪组织分泌的重要细胞因子，可增加肥胖患者的心血管风险，并最终导致器官损害。我们最近证实，肿瘤坏死因子-能降低Cyp2c衍生的环氧二十碳三烯酸(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作用。一种可能将肿瘤坏死因子和环氧化物与内皮功能障碍和肾脏损伤联系起来的信号通路是NFB激活细胞黏附分子，如MCP-1。肿瘤坏死因子-1、环氧二十烷类化合物和NFB在肥胖和高血压慢性肾脏疾病进展中的作用尚未阐明。因此，我们将检验这一假说，即肥胖和高血压患者中增加的肿瘤坏死因子-α、减少的环氧化物和增加的单核细胞趋化蛋白-1有助于肾血管损伤。我们将测定高脂饮食诱导的肥胖对高血压动物的传入小动脉功能、血压和肾脏损伤的影响。目前的提案将定义肿瘤坏死因子-1、内源性内毒素、神经营养因子和单核细胞趋化蛋白-1的贡献，以及这些途径在肥胖和高血压中的相互作用。这项建议结合了新的代谢氧脂图谱、RT-PCR阵列和对细胞机制的有针对性的分析，这将使我们能够对导致肥胖和高血压肾脏疾病进展的机制有独特的见解。总之，这一应用中拟议的实验将为肥胖和高血压中慢性肾脏疾病的进展提供新的机制洞察力。 项目简介：世界卫生组织最近将肥胖列为全球首要健康问题之一。慢性肾脏疾病增加的主要原因之一是肥胖相关糖尿病的增加及其与高血压的共存。该项目将检验这样一种假设，即脂肪酸代谢产物和炎症分子之间的相互作用会加速肥胖和高血压患者慢性肾脏疾病的进展。总体而言，本应用中提出的实验将为肥胖和高血压慢性肾脏疾病的治疗提供新的见解和治疗靶点。

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.