TRPC-mediated calcium signaling in podocytes

项目总结 蛋白尿是一个主要的保健问题，不仅是肾脏的主要标志和预后标志 这不仅是心血管疾病的危险因素，也是心血管疾病发病率和死亡率的独立风险因素。 肾足细胞对维持肾滤过屏障非常重要。早期足细胞损伤是 特点是钙离子信号转导失调，导致蛋白尿、蛋白不适当渗漏 进入尿液中。 PI和其他人的研究表明，由Trp(瞬时受体电位)介导的钙信号 通道，在迁移细胞的前沿附近富含。PI实验室正在进行的工作表明 足细胞内钙离子通过TRPC5和TRPC6通道的内流对细胞骨架至关重要 这些细胞的完整性。TRPC5介导的钙内流诱导rac1激活，从而促进足细胞 迁移。相反，TRPC6介导的钙内流增加了RhoA活性，抑制了足细胞的迁移。 在这里，我们建议测试我们的中心假设，即破坏TRPC5和TRPC5之间的关键平衡 TRPC6信号参与了蛋白尿的发病机制。我们特别感兴趣的是 蛋白尿性肾病早期的TRPC5和rac1信号转导。为了检验这一假设，我们的首要目标是 是探索TRPC通道是否通过调节突触素和RhoGTP酶来调节肌动蛋白的动态 活动(以足细胞为单位)。在我们的第二个目标中，我们将探索足细胞TRPC5信号在体内的作用 蛋白尿的发病机制，因此它可能成为肾病等疾病的新治疗靶点 综合征、FSGS、糖尿病和高血压肾病。 这一研究领域目前与人类疾病高度相关，因为TRPC介导的足细胞损伤 导致蛋白尿，而蛋白尿又是慢性肾脏疾病和肾衰竭的先兆，两者都是 它们正在上升，最近被许多观察家描述为一种即将到来的流行病。 好了！ 好了！

PROJECT SUMMARY Proteinuria is a major health-care problem, not only as a cardinal sign and prognostic marker of kidney disease, but also importantly, as an independent risk factor for cardiovascular morbidity and mortality. Kidney podocytes are important for the maintenance of the kidney filtration barrier. Early podocyte injury is characterized by dysregulation of Ca2+ signaling, leading to proteinuria, the inappropriate leakage of protein into the urine. Work by the PI and others has shown that Ca2+ signals, mediated by TRP (Transient Receptor Potential) channels, are enriched near the leading edge of migrating cells. Ongoing work in the PI's laboratory has shown that Ca2+ influx through TRPC5 and TRPC6 channels in podocytes is criticaly important for the cytoskeletal integrity of these cells. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocyte migration. In contrast, TRPC6-mediated Ca2+ influx increases RhoA activity, inhibiting podocyte migration. Here we propose to test our central hypothesis that disruption of the critical balance between TRPC5 and TRPC6 signaling contributes to the pathogenesis of proteinuria. We are specificaly interested in the role of TRPC5 and Rac1 signaling in early phases of proteinuric kidney disease. To test this hypothesis, our first aim is to explore whether TRPC channels regulate actin dynamics by modulating synaptopodin and RhoGTPase activity in podocytes. In our second aim, we wil explore the in vivo role of podocyte TRPC5 signaling in the pathogenesis of proteinuria, and thus its potential as a new therapeutic target for diseases such as nephrotic syndrome, FSGS, diabetic and hypertensive nephropathy. This area of research is currently highly relevant to human disease, since TRPC-mediated podocyte damage leads to proteinuria, and in turn, proteinuria is a herald of chronic kidney disease and kidney failure, both of which are on the rise, and have been recently described by many observers as an impending epidemic. ! !