Induction of TRPC6 channel in acquired forms of proteinuric kidney disease
Induction of TRPC6 channel in acquired forms of proteinuric kidney disease
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DOI：
10.1681/asn.2006091010
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发表时间：
2007-01-01
影响因子：
13.6
通讯作者：
Reiser, Jochen
中科院分区：
文献类型：
--
作者：
Moeller, Clemens C.;Wei, Changli;Reiser, Jochen
足细胞及其裂孔隔膜的损伤通常导致显著的蛋白尿。TRPC6基因编码一个与狭缝通道相关的阳离子渗透性离子通道，最近已显示TRPC6基因突变与遗传性进行性肾衰竭共分离。本文显示野生型TRPC 6的诱导表达是人蛋白尿肾病的共同特征，在膜性肾病中观察到最高的诱导。暴露于补体的培养足细胞上调TRPC 6蛋白。嘌呤霉素氨基糖苷处理的足细胞中受体操作通道的刺激导致钙内流以时间和剂量依赖性方式增加。从机制上讲，TRPC 6在功能上与足细胞肌动蛋白细胞骨架连接，后者在TRPC 6过表达时重排。瞬时体内基因传递TRPC 6进入小鼠导致TRPC 6蛋白在裂孔隔膜处表达并引起蛋白尿。这些研究表明TRPC 6参与了非遗传性蛋白尿疾病的病理学。
Injury to podocytes and their slit diaphragms typically leads to marked proteinuria. Mutations in the TRPC6 gene that codes for a slit diaphragm-associated, cation-permeable ion channel have been shown recently to co-segregate with hereditary forms of progressive kidney failure. Herein is shown that induced expression of wild-type TRPC6 is a common feature of human proteinuric kidney diseases, with highest induction observed in membranous nephropathy. Cultured podocytes that are exposed to complement upregulate TRPC6 protein. Stimulation of receptor-operated channels in puromycin aminonucleoside-treated podocytes leads to increased calcium influx in a time- and dosage-dependent manner. Mechanistically, it is shown that TRPC6 is functionally connected to the podocyte actin cytoskeleton, which is rearranged upon overexpression of TRPC6. Transient in vivo gene delivery of TRPC6 into mice leads to expression of TRPC6 protein at the slit diaphragm and causes proteinuria. These studies suggest the involvement of TRPC6 in the pathology of nongenetic forms of proteinuric disease.