부산대학교 도서관

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 [VEGF.sub.164] isoform, and the antiangiogenic [VEGF.sub.165]b isoform in mature, adult glomeruli in vivo using conditional, inducible transgenic overexpression systems in mice. Podocyte-specific [VEGF.sub.164] overexpression (up to 100 days) was induced by oral administration of doxycycline to adult podocin-rtTA/TetO-[VEGF.sub.164] double transgenic mice. The consequences of simultaneous overexpression of [VEGF.sub.164] and [VEGF.sub.165b] were assessed in triple-transgenic podocin-rtTA/TetO-[VEGF.sub.164]/nephrin-[VEGF.sub.165]b mice. Persistent [VEGF.sub.164] overexpression did not cause proteinuria but did increase glomerular ultrafiltration coefficient between days 3 and 7. Despite persistently increased VEGFI64 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 [VEGF.sub.164]-overexpressing mice. The changes in glomerular ultrafiltration coefficient and SPS coverage induced by 7 days of overexpression of [VEGF.sub.164] were not present in triple transgenic [VEGF.sub.164] and [VEGF.sub.165]b overexpressing mice. These results indicate that 1) the adult mouse glomerulus is relatively resistant to induced [VEGF.sub.164] overexpression. [VEGF.sub.164] 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. [VEGF.sub.165]b is capable of preventing [VEGF.sub.164]-induced changes in glomerular permeability and ultrastructure in vivo. glomerulus; permeability; VEGF; proteinuria; podocyte doi: 10.1152/ajprenal.00410.2011.