Abstract
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. We reported 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.
Highlights
Phospholipase A2 (PLA2)4 enzymes catalyze the cleavage of the sn-2-ester bond of phospholipids to yield free fatty acids, such as arachidonic acid, and lysophospholipids [1,2,3]
We show that deletion of independent PLA2s (iPLA2s)␥ did not cause detectable albuminuria; it resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes as well as loss of podocytes in aging KO mice
We demonstrated that deletion of iPLA2␥ resulted in striking mitochondrial abnormalities in glomerular epithelial cells (GECs)/ podocytes of 10 –11-month-old mice (Fig. 2)
Summary
Phospholipase A2 (PLA2) enzymes catalyze the cleavage of the sn-2-ester bond of phospholipids to yield free fatty acids, such as arachidonic acid, and lysophospholipids [1,2,3]. IPLA2␥ deletion induced profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis, resulting in enlarged and degenerating mitochondria, leading to enhanced autophagy and cognitive dysfunction [8]. Another recent study showed that genetic ablation of iPLA2␥ prevented obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation [9]. Podocyte Injury in iPLA2␥ Knock-out Mice ment, are associated with podocyte injury, which may lead to foot process effacement, detachment from the GBM, or apoptosis, with consequent impairment of glomerular function and permselectivity (proteinuria), and glomerulosclerosis (13, 16 –18)
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