Department of Biochemistry, University of Hyderabad, Hyderabad, 500046, India.
Department of Biotechnology & Bioinformatics, University of Hyderabad, Hyderabad, 500046, India.
Sci Rep. 2019 Nov 29;9(1):17897. doi: 10.1038/s41598-019-52872-5.
Podocytes are specialized cells of the glomerulus and key component of the glomerular filtration apparatus (GFA). GFA regulates the permselectivity and ultrafiltration of blood. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. We investigated the mechanism of ischemic hypoxia-induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1α in the podocytes that resulted in the increased expression of ZEB2 (Zinc finger E-box-binding homeobox 2). ZEB2, in turn, induced TRPC6 (transient receptor potential cation channel, subfamily C, member 6), which has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK) in podocytes. FAK activation resulted in the stress fibers reorganization and podocyte foot process effacement. Our study suggests overactive HIF1α/ZEB2 axis during ischemic-hypoxia raises intracellular calcium levels via TRPC6 and consequently altered podocyte structure and function thus contributes to proteinuria.
足细胞是肾小球的特化细胞，也是肾小球滤过装置（GFA）的关键组成部分。GFA 调节血液的选择性过滤和超滤。在缺血性中风期间，GFA 的完整性受到损害并表现为蛋白尿的机制仍然是个谜。我们在大脑中动脉闭塞（MCAO）模型中研究了缺血缺氧诱导蛋白尿的机制。缺血缺氧导致足细胞中 HIF1α 的积累，从而导致 ZEB2（锌指 E 盒结合同源盒 2）的表达增加。ZEB2 反过来诱导 TRPC6（瞬时受体电位阳离子通道，亚家族 C，成员 6），其对钙的选择性增加。TRPC6 的高表达引起钙内流增加和足细胞中粘着斑激酶（FAK）的异常激活。FAK 的激活导致应力纤维重排和足细胞足突消失。我们的研究表明，缺血缺氧期间过度活跃的 HIF1α/ZEB2 轴通过 TRPC6 升高细胞内钙水平，进而改变足细胞的结构和功能，从而导致蛋白尿。
