Adiponectin and Podocytes

描述（由申请人提供）： 我们最近发现，在肥胖的非裔美国人中，循环脂联素水平与白蛋白尿呈负相关。由于肾脏疾病的发病率在非洲裔美国人中极高，肥胖相关肾脏疾病的机制尚不清楚，我们的建议将集中在这个对VA人群非常重要的话题上。足细胞似乎是脂联素赋予其保护作用的主要靶细胞。在目前的建议中，我们将确定脂联素受体和信号通路，脂联素赋予足细胞的好处，并检查脂联素在调节一种酶称为AMPK的关键作用。我们已经确定，AMPK在脂联素缺乏小鼠和糖尿病小鼠的足细胞中减少。给予脂联素可恢复AMPK活性，并保护足细胞免受蛋白尿的影响。AMPK在足细胞上的一个关键靶标似乎是蛋白ZO-1，其已被证明密切参与足细胞足突与肾小球基底膜的粘附。该提案旨在确定足细胞上脂联素的关键信号受体，确定AMPK的作用，并确定脂联素和AMPK调节的蛋白质。这些研究将直接受益于VA人群，因为现有的药物可以调节脂联素水平及其信号通路，因此可能为这一肾脏疾病高风险人群提供新的治疗方法。 公共卫生相关性： 有超过60-80万美国人患有肥胖症，糖尿病和高血压。他们中的许多人有早期肾脏疾病的证据。我们最近发现，脂肪细胞产生的一种称为脂联素的激素似乎是肥胖患者早期肾脏疾病的主要原因。我们最近的研究已经确定足细胞是脂联素作用的关键靶细胞。我们的研究将确定脂联素在肾脏足细胞中的作用。通过了解脂联素、其受体、AMPK和ZO-1之间的关系，我们预计将出现新的治疗方法，可以在早期治疗这些患者。调节AMPK通路的可用药物的可用性表明了我们工作的翻译潜力。

DESCRIPTION (provided by applicant): Project Summary/Abstract We have recently identified that circulating adiponectin levels negatively correlate with albuminuria in obese African Americans. As the incidence of kidney disease is extremely high in African Americans and the mechanisms of obesity related kidney disease are unclear, our proposal will focus on this highly significant topic to the VA population. The podocyte appears to be the main target cell by which adiponectin confers its protective action. In the present proposal we will identify the adiponectin receptors and signaling pathways by which adiponectin confers benefits to the podocytes and examine the key role of adiponectin in regulating an enzyme called AMPK. We have identified that AMPK is decreased in adiponectin deficient mice and in podocytes from diabetic mice. Administration of adiponectin restores AMPK activity and appears to protect podocytes from albuminuria. A key target of AMPK on podocytes appears to be the protein ZO-1 which has been shown to be intimately involved in the adherence of the podocyte foot processes to the glomerular basement membrane. The proposal aims to identify the key signaling receptors for adiponectin on podocytes, identify the role of AMPK and identify the proteins regulated by adiponectin and AMPK in mice. The studies will be of direct benefit to the VA population as there are existing drugs that regulate adiponectin levels and its signaling pathways, and thus may potentially offer new therapies for this population that is at high risk for kidney disease. PUBLIC HEALTH RELEVANCE: Project Narrative There are over 60-80 million Americans with obesity, diabetes and hypertension. Many of them have evidence of early kidney disease. We have recently identified that a hormone produced by the fat cells, called adiponectin appears to be a major contributor to the early kidney disease seen in patients with obesity. Our recent studies have identified that the podocyte is a key target cell of adiponectin action. Our studies will determine the role of adiponectin in podocytes of the kidney. By understanding the relationships between adiponectin, its receptors, AMPK and ZO-1 we expect that new treatments will arise that can treat these patients at early stages. The availability of available drugs that regulate the AMPK pathway is an indication of the translation potential of our work.