Angiotensin II down-regulates nephrin-Akt signaling and induces podocyte injury: roleof c-Abl.
Angiotensin II down-regulates nephrin-Akt signaling and induces podocyte injury: roleof c-Abl.
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血管紧张素 II 下调 nephrin-Akt 信号传导并诱导足细胞损伤：c-Abl 的作用
DOI：
10.1091/mbc.e15-04-0223
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发表时间：
2016-01-01
影响因子：
3.3
通讯作者：
Ding G
中科院分区：
文献类型：
--
作者：
Yang Q;Ma Y;Liu Y;Liang W;Chen X;Ren Z;Wang H;Singhal PC;Ding G
血管紧张素转换酶II在蛋白尿性肾脏疾病的发生和发展中起重要作用，但其机制仍不清楚。结果表明，c-Abl是newitin信号转导和SHIP2-Akt通路的分子伴侣，其释放的c-Abl参与了Ang II诱导的足细胞损伤。最近的研究表明，neparin在血管紧张素II(Ang II)诱导的足细胞损伤中起着至关重要的作用，从而导致蛋白尿的发生和肾脏疾病的进展，但其具体机制尚不清楚。C-Abl是一种含有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的调节。C-Abl是一种下游信号转导分子，可以与含有SH2/SH3结构域的分子相互作用。在此，我们报告了注射血管紧张素II的大鼠出现蛋白尿和足细胞损伤，并伴有neparin去磷酸化和neparin与c-Abl之间的微小相互作用。在体外，血管紧张素II诱导足细胞损伤，并伴随着neparin和Akt的去磷酸化，同时与c-Abl之间的相互作用很小。此外，Ang II还促进c-Abl的磷酸化和c-Ab1与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)对Ang II诱导的足细胞损伤具有保护作用，抑制Ang II诱导的c-Abl-SHIP2相互作用和SHIP2磷酸化，并维持稳定的neparin磷酸化水平。这些结果表明，c-Abl是neparin信号和SHIP2-Akt通路的分子伴侣，c-Abl的释放参与了Ang II诱导的足细胞损伤。
Ang II plays a vital role in the initiation and progression of proteinuric kidney diseases, but the mechanism is still elusive. It is shown that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway, and released c-Abl from nephrin is involved in Ang II–induced podocyte injury. 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.