Genetic Ablation of Calcium-independent Phospholipase A(2)γ Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice

Genetic ablation of calcium-independent phospholipase A(2)γ (iPLA(2)γ) in mice results in marked damage of mitochondria and enhanced autophagy in glomerular visceral epithelial cells (GECs) or podocytes. The present study addresses the role of iPLA(2)γ in glomerular injury. In adriamycin nephrosis, deletion of iPLA(2)γ exacerbated albuminuria and reduced podocyte number. Glomerular LC3-II increased and p62 decreased in adriamycin-treated iPLA(2)γ knockout (KO) mice, compared with treated control, in keeping with increased autophagy in KO. iPLA(2)γ KO GECs in culture also demonstrated increased autophagy, compared with control GECs. iPLA(2)γ KO GECs showed a reduced oxygen consumption rate and increased phosphorylation of AMP kinase (pAMPK), consistent with mitochondrial dysfunction. Adriamycin further stimulated pAMPK and autophagy. After co-transfection of GECs with mito-YFP (to label mitochondria) and RFP-LC3 (to label autophagosomes), or RFP-LAMP1 (to label lysosomes), there was greater colocalization of mito-YFP with RFP-LC3-II and with RFP-LAMP1 in iPLA(2)γ KO GECs, compared with WT, indicating enhanced mitophagy in KO. Adriamycin increased mitophagy in WT cells. Thus, iPLA(2)γ has a cytoprotective function in the normal glomerulus and in glomerulopathy, as deletion of iPLA(2)γ leads to mitochondrial damage and impaired energy homeostasis, as well as autophagy and mitophagy.