Yang Qian, Ma Yiqiong, Liu Yipeng, Liang Wei, Chen Xinghua, Ren Zhilong, Wang Huiming, Singhal Pravin C, Ding Guohua
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore-Long Island Medical School, Great Neck, NY 11021.
Mol Biol Cell. 2016 Jan 1;27(1):197-208. doi: 10.1091/mbc.E15-04-0223. Epub 2015 Oct 28.
Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)-induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain-containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II-infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain-containing 5'-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II-induced podocyte injury, suppressed the Ang II-induced c-Abl-SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II-induced podocyte injury.
最近的研究表明，nephrin在血管紧张素II（Ang II）诱导的足细胞损伤中起关键作用，从而导致蛋白尿的发生和肾脏疾病的进展，但其具体机制仍不清楚。c-Abl是一种含SH2/SH3结构域的非受体酪氨酸激酶，参与细胞存活和细胞骨架调节。磷酸化的nephrin能够与含SH2/SH3结构域的分子相互作用，这表明c-Abl可能是nephrin信号传导的下游分子。在此我们报告，输注Ang II的大鼠出现蛋白尿和足细胞损伤，伴有nephrin去磷酸化以及nephrin与c-Abl之间的相互作用减弱。在体外，Ang II诱导足细胞损伤以及nephrin和Akt去磷酸化，这与nephrin和c-Abl之间的相互作用减弱同时发生。此外，Ang II促进c-Abl磷酸化以及c-Abl与含SH2结构域的5'-肌醇磷酸酶2（SHIP2）之间的相互作用。c-Abl小干扰RNA（siRNA）和STI571（c-Abl抑制剂）可保护足细胞免受Ang II诱导的损伤，抑制Ang II诱导的c-Abl-SHIP2相互作用和SHIP2磷酸化，并维持nephrin磷酸化的稳定水平。这些结果表明，c-Abl是nephrin信号传导和SHIP2-Akt途径的分子伴侣，释放的c-Abl促成了Ang II诱导的足细胞损伤。
