sPLA2‐IB and PLA2R mediate insufficient autophagy and contribute to podocyte injury in idiopathic membranous nephropathy by activation of the p38MAPK/mTOR/ULK1 ser757 signaling pathway

Abstract Secretory phospholipase A2 group IB (sPLA2‐IB) and M‐type phospholipase A2 receptor (PLA2R) are closely associated with proteinuria in idiopathic membranous nephropathy (IMN). Podocytes constitute an important component of glomerular filtration, and high basal autophagy is indispensable for podocyte function. The current study aimed to analyze the relationship between sPLA2‐IB and podocyte autophagy in IMN and determine whether sPLA2‐IB mediates abnormal autophagy regulation in podocytes. The serum sPLA2‐IB level and podocyte autophagy were detected, and clinical data were collected from IMN patients with different proteinuria levels. Then, the effects of sPLA2‐IB on autophagy signaling pathways were evaluated in cultured human podocytes treated with sPLA2‐IB, rapamycin, p38 inhibition, and PLA2R‐siRNA in vitro. We found that IMN patients with nephrotic‐range proteinuria have a significantly higher level of sPLA2‐IB and fewer autophagosomes than those with non‐nephrotic‐range proteinuria. In vitro sPLA2‐IB–induced insufficient autophagy in podocytes and promoted podocyte injury via activation of the mTOR/ULK1 ser757 signaling pathway. Moreover, inhibition of p38 MAPK evidently abrogated sPLA2‐IB–induced autophagy and the activation of mTOR/ULK1 ser757 . Additionally, PLA2R silencing demonstrated that sPLA2‐IB–induced abnormal autophagy was also PLA2R‐dependent. In conclusion, the results revealed that sPLA2‐IB downregulated autophagy and contributed to podocyte injury via PLA2R though activation of the p38MAPK/mTOR/ULK1 ser757 signaling pathway.