Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGFKD diabetic mice with intact eNOS, whereas VEGFKD induction in eNOS−/−:VEGFKD mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Here, NOS3 is linked to acute kidney injury.