Excessive arachidonic acid induced actin bunching remodeling and podocyte injury via a PKA-c-Abl dependent pathway
Excessive arachidonic acid induced actin bunching remodeling and podocyte injury via a PKA-c-Abl dependent pathway
复制标题
过量花生四烯酸通过 PKA-c-Abl 依赖性途径诱导肌动蛋白束重塑和足细胞损伤
DOI：
10.1016/j.yexcr.2019.111808
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发表时间：
2020
影响因子：
3.7
通讯作者：
Wan Jianxin
中科院分区：
文献类型：
--
作者：
Yang Liyan;Pan Yangbin;Wu Yuansheng;Lin Songhua;Dai Binbin;Chen Hong;Wan Jianxin
最近的研究表明，血清分泌型磷脂酶A2 IB组（sPLA 2-IB）与蛋白尿性肾病相关，并通过其天然受体在足细胞损伤中起关键作用。花生四烯酸（AA）作为sPLA 2-IB的主要代谢产物，调节肌动蛋白的重构，参与足细胞的损伤。然而，AA在调节足细胞肌动蛋白重塑和人足细胞损伤中的潜在机制尚不清楚。本文报道了AA诱导F-actin细胞骨架环形成，促进蛋白激酶A（PKA）、nephrin和c-Abl磷酸化。此外，AA还通过与c-Abl的相互作用促进c-Abl从细胞核向细胞质的移位，并增加c-Abl向β-nephrin的募集。H89（PKA抑制剂）对AA诱导的F-actin聚束重构提供保护，下调nephrin磷酸化，并抑制c-Abl易位和活化。STI 571（c-Abl抑制剂）也改善AA相关的F-肌动蛋白聚束重构。此外，H89和STI 571均能减轻足细胞的凋亡和粘附损伤。这些结果表明，过量的AA处理对足细胞肌动蛋白细胞骨架是有害的，并且由于PKA-c-Abl信号传导的激活而促进足细胞损伤。
Recent studies have shown that serum secretory phospholipase A2 group IB (sPLA2-IB) is associated with proteinuric kidney diseases and plays a pivotal role in podocyte injury via its natural receptor. Arachidonic acid (AA), as a major metabolite of sPLA2-IB, regulates the actin bungling remodeling and contributes to the podocyte injury. However, the underlying mechanism of AA in the regulation of podocyte actin remodeling and human podocyte injury is unclear. Here, we reported that AA induced F-actin cytoskeletal ring formation and promoted protein kinase A (PKA), nephrin and c-Abl phosphorylation. Moreover, AA promoted c-Abl translocation from the nucleus to the cytoplasm and increased the recruitment of c-Abl to p-nephrin by the interaction between them. H89 (PKA inhibitor) provided protection against AA-induced F-actin bunching remodeling, down-regulated nephrin phosphorylation, and suppressed the c-Abl translocation and activation. STI571 (c-Abl inhibitor) also improved the AA associated F-actin bunching remodeling. In addition, H89 and STI571 both alleviated apoptosis and adhesion damage of podocyte. These results indicate that an excess of AA treatment is detrimental to the podocyte actin cytoskeleton and promotes podocyte injury due to the activation of PKA-c-Abl signaling.