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.

中文翻译：

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过量的花生四烯酸通过PKA-c-Abl依赖性途径诱导肌动蛋白聚集重塑和足细胞损伤。

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足细胞损伤中起关键作用。花生四烯酸（AA）作为sPLA2-IB的主要代谢产物，调节肌动蛋白的重塑，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类足细胞损伤中的潜在机制尚不清楚。在这里，我们报道了AA诱导F-肌动蛋白细胞骨架环形成并促进了蛋白激酶A（PKA），肾素和c-Abl磷酸化。此外，AA促进了c-Abl从细胞核到细胞质的转运，并通过它们之间的相互作用增加了c-Abl向p-nephrin的募集。H89（PKA抑制剂）可针对AA诱导的F-肌动蛋白束聚重塑提供保护，下调肾素的磷酸化，并抑制c-Abl易位和激活。STI571（c-Abl抑制剂）还改善了AA相关的F-肌动蛋白束重塑。另外，H89和STI571都减轻了足细胞的凋亡和粘附损伤。这些结果表明过量的AA治疗对足细胞肌动蛋白细胞骨架有害，并且由于PKA-c-Abl信号传导的激活而促进足细胞损伤。