Molecular mechanisms of AT1R signaling in FSGS

描述（由申请人提供）：经典研究揭示了肾素-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（ARBs）是迄今为止延缓疾病进展的首选治疗方法。以蛋白尿、足突消退（FPE）和裂隙横膈膜破坏（SD）为代表的足细胞功能障碍，往往是导致进行性肾脏疾病的最初损害。人类Ca2+渗透离子通道TRPC6突变是遗传性局灶节段性肾小球硬化（FSGS）的原因，这一发现将Ca2+生物学带到了足细胞研究的前沿。我们最近发表的研究表明，TRPC5和TRPC6都是足细胞中重要的Ca2+内流途径。肾素-血管紧张素系统（RAS）和RAS/Ca2+信号对足细胞的结构和功能完整性至关重要。大鼠足细胞特异性血管紧张素II型1受体（AT1R Tg）的转基因过表达可导致足细胞肥大、蛋白尿和最终的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AT1R激活和随后的Ca2+通过TRPC5和TRPC6通道内流足细胞之间的机制联系。trpc5介导的Ca2+内流诱导Rac1激活，从而促进足细胞迁移。CsA可以挽救TRPC5介导的突触肽降解和应力纤维的丢失，将TRPC5置于足细胞中钙调磷酸酶介导的信号传导的上游。在这里，我们提出验证我们的假设，即at1r介导的TRPC5激活导致csa敏感的蛋白尿和足细胞肥大。在晚期，TRPC6丰度的上调导致过量的Ca2+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世界数百万人的主要卫生保健问题，目前临床上没有靶向的、保留足细胞的治疗方法。

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.