Effects of podocyte injury on glomerular development

To study the effects of podocyte injury on glomerular maturation and underlying mechanisms of such effects, puromycin aminonucleoside (PAN) was given to neonatal mice at 1 d post partum (1 dpp). Mice with PAN injection had smaller kidney weight (KW) and body weight (BW) at all times and smaller KW/BW at 4, 8, and 12 dpp versus normal saline (NS) controls. Electron microscopy (EM) revealed nearly complete podocyte foot process effacement and segmental microvillous transformation as early as 2 dpp, preceding proteinuria. PAN-injected kidneys showed significantly fewer glomerular capillary loops and decreased glomerular maturation index, as well as less CD31+ endothelium in cortical glomeruli at 12 dpp versus NS controls. Glomerular mesangial injury and glomerulosclerosis along with proteinuria were noted in PAN-injected kidneys starting from 30 dpp. Systolic blood pressure was increased significantly by 60 dpp in PAN mice. PAN mice also had significantly decreased Flk-1 and Tie2 mRNA expression and increased angiopoitein-1 (Ang-1) expression, without change in vascular endothelial growth factor (VEGF) at 2 dpp versus NS. Our study shows that podocyte injury in neonatal mice kidneys alters the expression of key capillary growth modulators in glomeruli, leading to abnormal development of glomerular capillaries, with subsequent development of proteinuria, hypertension, and glomerulosclerosis.