Genetic ablation of calcium-independent phospholipase A₂γ induces glomerular injury in mice

Glomerular visceral epithelial cells (podocytes) play a critical role in the maintenance of glomerular permselectivity. Podocyte injury, manifesting as proteinuria, is the cause of many glomerular diseases.Wereported previously that calcium-independent phospholipase A₂γ (iPLA₂γ) is cytoprotective against complement-mediated glomerular epithelial cell injury. Studies in iPLA₂γ KO mice have demonstrated an important role for iPLA₂γ in mitochondrial lipid turnover, membrane structure, and metabolism. The aim of the present study was to employ iPLA₂γ KO mice to better understand the role of iPLA₂γ in normal glomerular and podocyte function as well as in glomerular injury. We show that deletion of iPLA₂γ did not cause detectable albuminuria; however, it resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes as well as loss of podocytes in aging KO mice. Moreover, after induction of anti-glomerular basement membrane nephritis in young mice, iPLA₂γ KO mice exhibited significantly increased levels of albuminuria, podocyte injury, and loss of podocytes compared with wild type. Thus, iPLA₂γ has a protective functional role in the normal glomerulus and in glomerulonephritis. Understanding the role of iPLA₂γ in glomerular pathophysiology provides opportunities for the development of novel therapeutic approaches to glomerular injury and proteinuria.