VEGF165b overexpression restores normal glomerular water permeability in VEGF164-overexpressing adult mice

Vascular endothelial growth factor (VEGF)-A, a family of differentially spliced proteins produced by glomerular podocytes, maintains glomerular filtration barrier function. The expression of VEGF molecules is altered in human nephropathy. We aimed to determine the roles of the angiogenic VEGF164 isoform, and the antiangiogenic VEGF165b isoform in mature, adult glomeruli in vivo using conditional, inducible transgenic overexpression systems in mice. Podocyte-specific VEGF164 overexpression (up to 100 days) was induced by oral administration of doxycycline to adult podocin-rtTA/TetO-VEGF164 double transgenic mice. The consequences of simultaneous overexpression of VEGF164 and VEGF165b were assessed in triple-transgenic podocin-rtTA/TetO-VEGF164/nephrin-VEGF165b mice. Persistent VEGF164 overexpression did not cause proteinuria but did increase glomerular ultrafiltration coefficient between days 3 and 7. Despite persistently increased VEGF164 levels, glomerular ultrafiltration coefficient normalized by day 14 and remained normal up to 100 days. Decreased subpodocyte space (SPS) coverage of the glomerular capillary wall accompanied increased glomerular hydraulic conductivity in VEGF164-overexpressing mice. The changes in glomerular ultrafiltration coefficient and SPS coverage induced by 7 days of overexpression of VEGF164 were not present in triple transgenic VEGF164 and VEGF165b overexpressing mice. These results indicate that 1) the adult mouse glomerulus is relatively resistant to induced VEGF164 overexpression. VEGF164 overexpression altered glomerular permeability but did not cause proteinuria in these mature, adult animals; 2) the SPS is a dynamic VEGF-responsive modulator of glomerular function; and 3) the balance of VEGF isoforms plays a critical role in the regulation of glomerular permeability. VEGF165b is capable of preventing VEGF164-induced changes in glomerular permeability and ultrastructure in vivo.