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Abstract: SA-PO239

Deletion of iPLA2γ Protects Mice From Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Cybulsky, Andrey V., McGill University Health Centre, Montreal, Quebec, Canada
  • Guillemette, Julie, McGill University Health Centre, Montreal, Quebec, Canada
  • Papillon, Joan, McGill University Health Centre, Montreal, Quebec, Canada
  • Navarro-Betancourt, José R., McGill University Health Centre, Montreal, Quebec, Canada
  • Elimam, Hanan, McGill University Health Centre, Montreal, Quebec, Canada
  • Fantus, Ivan George, McGill University Health Centre, Montreal, Quebec, Canada

Calcium-independent phospholipase A2γ (iPLA2γ) 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 iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis (GN; anti-glomerular basement membrane GN and adriamycin nephrosis), deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy.


Hyperglycemia was induced in male mice (mean age 6.5 months) with streptozotocin (STZ). Cultured GECs were produced from control and iPLA2γ KO mice; the GECs express synaptopodin and nephrin.


STZ induced progressive albuminuria in control (Ctrl) mice (~5 mg/mg creatinine at 21 weeks), while albuminuria did not increase in iPLA2γ KO mice (~0.5 mg/mg creatinine), remaining comparable to untreated groups (9-15 mice/group). Despite similar exposure to STZ, the STZ-KO mice developed a lower level of hyperglycemia compared to STZ-Ctrl. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in STZ-Ctrl mice (20%). Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in Ctrl-STZ compared to KO-STZ mice. Glomerular LC3-II (a marker of autophagy) was increased in KO and KO-STZ mice compared to respective Ctrl groups. Glomerular matrix was expanded in both Ctrl-STZ and KO-STZ groups. STZ did not alter podocyte number, nor amounts of glomerular synaptopodin, nephrin, podocalyxin, F-actin, and macrophages. Treatment of cultured GECs with H2O2 resulted in increased cell death in Ctrl GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with 18 mM glucose compared to 8 mM. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin.


In contrast to acute GN, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This may be related at least in part to increased glomerular autophagy.


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