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bioRxiv · 10.1101/2024.04.26.591364

Genetic Deletion of Calcium-independent Phospholipase A2γ Protects Mice from Diabetic Nephropathy

Cybulsky, A. V.·Papillon, J.·Guillemette, J.·Navarro-Betancourt, J. R.·Elimam, H.·Fantus, I. G.
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Abstract

Calcium-independent phospholipase A2{gamma} (iPLA2{gamma}) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2{gamma} in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis, deletion of iPLA2{gamma} exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2{gamma} in diabetic nephropathy. Hyperglycemia was induced in male mice with streptozotocin (STZ). STZ induced progressive albuminuria in control mice (over 21 weeks), while albuminuria did not increase in iPLA2{gamma} KO mice, remaining comparable to untreated groups. Despite similar exposure to STZ, the STZ-treated iPLA2{gamma} KO mice developed a lower level of hyperglycemia compared to STZ-treated control. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even iPLA2{gamma} KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in diabetic control mice. Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in diabetic control compared to diabetic iPLA2{gamma} KO mice. Glomerular matrix was expanded in diabetic mice, with control exceeding iPLA2{gamma} KO. Glomerular autophagy (increased LC3-II and decreased p62) was enhanced in diabetic iPLA2{gamma} KO mice compared to control. Treatment of cultured GECs with H2O2 resulted in increased cell death in control GECs compared to iPLA2{gamma} KO, and the increase was slightly greater in medium with high glucose compared to low glucose. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. In conclusion, mice with global deletion of iPLA2{gamma} are protected from developing chronic glomerular injury in diabetic nephropathy. This is associated with increased glomerular autophagy.

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Cybulsky, A. V., Papillon, J., Guillemette, J., Navarro-Betancourt, J. R., Elimam, H., Fantus, I. G.. 2024-04-29. Genetic Deletion of Calcium-independent Phospholipase A2γ Protects Mice from Diabetic Nephropathy. https://doi.org/10.1101/2024.04.26.591364

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