Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Nephrology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
Exp Cell Res. 2020 Mar 15;388(2):111808. doi: 10.1016/j.yexcr.2019.111808. Epub 2019 Dec 28.
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.
最近的研究表明，血清分泌型磷脂酶 A2 组 IB（sPLA2-IB）与蛋白尿性肾脏疾病有关，并通过其天然受体在 podocyte 损伤中发挥关键作用。花生四烯酸（AA）作为 sPLA2-IB 的主要代谢物，调节肌动蛋白纠缠重塑，并导致足细胞损伤。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。在这里，我们报道 AA 诱导 F-actin 细胞骨架环形成，并促进蛋白激酶 A（PKA）、nephrin 和 c-Abl 磷酸化。此外，AA 促进 c-Abl 从核转位到细胞质，并通过它们之间的相互作用增加 c-Abl 募集到 p-nephrin。H89（PKA 抑制剂）提供了针对 AA 诱导的 F-actin 聚集重塑的保护，下调 nephrin 磷酸化，并抑制 c-Abl 易位和激活。STI571（c-Abl 抑制剂）也改善了 AA 相关的 F-actin 聚集重塑。此外，H89 和 STI571 均减轻了足细胞的凋亡和黏附损伤。这些结果表明，AA 处理过量会损害足细胞肌动蛋白细胞骨架，并通过激活 PKA-c-Abl 信号促进足细胞损伤。
