FIGURE 8.

Proposed model of podocyte VEGF^KD driven diffuse glomerulosclerosis in DM-VEGF^KD and eNOS:VEGF^KD mice. (A) Strong compensatory NO and thiol generation prevents GFR loss, attenuates proteinuria and diffuse glomerulosclerosis in diabetic VEGF^KD mice, while limitation of this compensatory mechanism in eNOS:VEGF^KD mice worsens the renal phenotype, leading to renal failure. (B) Reduced GSNOR S-nitrosylation increases GSNO and promotes increased S-nitrosylation of proteins, altering their signaling pathways: (C) decreased nephrin and VEGFR2 signaling and high SNO-β3-integrin inhibit β3-integrin activity leading to podocyte and endothelial cell injury; high SNO-laminin and low VEGFR2 signaling may contribute to the severe diffuse glomerulosclerosis described herein in eNOS:VEGF^KD + dox mice.