Molecular mechanisms of AT1R signaling in FSGS

描述（由申请人提供）：经典研究已经揭示了肾素-血管紧张素系统（RAS）在蛋白尿和慢性肾脏疾病的发生和进展中的核心作用。血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）是迄今为止延迟疾病进展的治疗选择。以蛋白尿、足突消失（FPE）和裂膈破裂（SD）为代表的足细胞功能障碍通常是导致进行性肾脏疾病的初始损伤。人类钙离子渗透性离子通道TRPC 6突变的鉴定是遗传性局灶节段性肾小球硬化症（FSGS）的原因，这将钙生物学带到了足细胞研究的最前沿。我们最近发表的工作表明，TRPC 5和TRPC 6都是足细胞中重要的Ca 2+内流途径。肾素-血管紧张素系统（RAS）和RAS/Ca 2+信号传导对足细胞的结构和功能完整性至关重要。足细胞特异性血管紧张素II 1型受体（AT 1 R Tg）在大鼠中的转基因过表达导致足细胞肥大、蛋白尿和最终FSGS，但导致疾病的分子机制尚不清楚。PI实验室的工作提供了AT 1 R激活和随后通过TRPC 5和TRPC 6通道在足细胞中的Ca 2+内流之间的机制联系。TRPC 5介导的Ca 2+内流诱导Rac 1活化，从而促进足细胞迁移。TRPC 5介导的突触足蛋白降解和应力纤维的丢失可以通过CsA来挽救，将TRPC 5置于足细胞中钙调神经磷酸酶介导的信号传导的上游。在这里，我们建议测试我们的假设，AT 1 R介导的TRPC 5激活导致CsA敏感性蛋白尿和足细胞肥大。在后期阶段，TRPC 6丰度的上调导致过量的Ca 2+毒性和足细胞死亡。这一研究领域与人类疾病高度相关，因为蛋白尿和相关肾脏疾病是影响全球数百万人的主要卫生保健问题，目前临床上没有靶向的足细胞保护疗法。

DESCRIPTION (provided by applicant): Classical studies have revealed a central role for the Renin-Angiotensin system (RAS) in the emergence and progression of proteinuria and chronic kidney disease. Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are to date the treatment of choice for the delay of disease progression. Podocyte dysfunction, represented by proteinuria, foot process effacement (FPE) and disruption of the slit diaphragm (SD), is often the initial insult leading to progressive kidney disease. The identification of human mutations in the Ca2+-permeable ion channel TRPC6 as a cause of inherited Focal Segmental Glomerulosclerosis (FSGS) brought Ca2+ biology to the forefront of podocyte research. Our recently published work revealed that both TRPC5 and TRPC6 are important Ca2+ influx pathways in podocytes. The Renin-Angiotensin system (RAS) and RAS/Ca2+ signaling is critical for the structural and functional integrity of podocytes. Podocyte-specific transgenic overexpression of the Angiotensin II type 1 receptor (AT1R) in rats (AT1R Tg) results in podocyte hypertrophy, proteinuria, and ultimately FSGS, but the molecular mechanisms leading to disease are not well understood. Work in the PI's laboratory provided a mechanistic link between AT1R activation and subsequent Ca2+ influx in podocytes through TRPC5 and TRPC6 channels. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocyte migration. TRPC5-mediated degradation of synaptopodin and loss of stress fibers can be rescued by CsA, placing TRPC5 upstream of calcineurin-mediated signaling in podocytes. Here we propose to test our hypothesis that AT1R-mediated activation of TRPC5 causes CsA-sensitive proteinuria and podocyte hypertrophy. At later stages, upregulation of TRPC6 abundance leads to excess Ca2+ toxicity and podocyte death. This area of research is highly relevant to human disease, because proteinuria and associated kidney disease is a major health-care problem affecting millions of people worldwide, and there are currently no targeted, podocyte-preserving therapies available in the clinic.