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 VEGF(164) isoform, and the antiangiogenic VEGF(165)b isoform in mature, adult glomeruli in vivo using conditional, inducible transgenic overexpression systems in mice. Podocyte-specific VEGF(164) overexpression (up to 100 days) was induced by oral administration of doxycycline to adult podocin-rtTA/TetO-VEGF(164) double transgenic mice. The consequences of simultaneous overexpression of VEGF(164) and VEGF(165)b were assessed in triple-transgenic podocin-rtTA/TetO-VEGF(164)/nephrin-VEGF(165)b mice. Persistent VEGF(164) overexpression did not cause proteinuria but did increase glomerular ultrafiltration coefficient between days 3 and 7. Despite persistently increased VEGF(164) 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(164)-overexpressing mice. The changes in glomerular ultrafiltration coefficient and SPS coverage induced by 7 days of overexpression of VEGF(164) were not present in triple transgenic VEGF(164) and VEGF(165)b overexpressing mice. These results indicate that 1) the adult mouse glomerulus is relatively resistant to induced VEGF(164) overexpression. VEGF(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(165)b is capable of preventing VEGF(164)-induced changes in glomerular permeability and ultrastructure in vivo.
Microvascular Research Laboratories, School of Physiology and Pharmacology, Univ. of Bristol, Preclinical Veterinary School, Southwell St., Bristol, United Kingdom. BS2 8EJ.
Sebastian
S
Oltean
Christopher R
CR
Neal
Athina
A
Mavrou
Panisha
P
Patel
Thomas
T
Ahad
Chloe
C
Alsop
Thomas
T
Lee
Karen
K
Sison
Yan
Y
Qiu
Steven J
SJ
Harper
David O
DO
Bates
Andrew H J
AH
Salmon
D000818:Animals; D001834:Body Water / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability; D050199:Podocytes / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse