A study of VEGF and its receptors in two rat models of proteinuria.
BACKGROUND
The high level of expression of vascular endothelial growth factor (VEGF) in normal podocyte foot processes suggests that VEGF has an important role in maintaining normal glomerular function. While altered VEGF expression occurs in many glomerular diseases, a direct role for VEGF in the pathogenesis of proteinuria has not been demonstrated.


METHODS
Expression of VEGF and its receptors (VEGFR-1 and VEGFR-2) was examined in passive Heymann nephritis (PHN) and puromycin aminonucleoside nephrosis (PAN), by immunohistochemistry, in situ hybridization, Northern and Western blotting. Inhibition of VEGF in the PAN model was performed by administration of a blocking antibody.


RESULTS
In both models, glomeruli showed upregulation of VEGF and VEGF receptors compared to control animals. VEGF mRNA was increased most significantly (5-fold) at day 5 after induction of PHN, prior to the onset of proteinuria, with persistent upregulation (3-fold) at day 21. Increased VEGF mRNA was also seen in PAN, but it was less marked. In situ hybridization and immunohistochemistry localized VEGF predominantly to podocytes. Increased expression of VEGFR-1 and VEGFR-2 protein was seen in glomerular endothelial cells of PHN and PAN rats by immunohistochemistry, as was VEGFR-2 mRNA by in situ hybridization. Upregulation of VEGFR-1 by endothelial cells was more striking in the PAN model than PHN. Administration of a blocking antibody to rats with PAN did not affect proteinuria, creatinine clearance or sodium excretion.


CONCLUSIONS
The expression of VEGF and its receptors is significantly increased in the PHN and PAN rat models of proteinuria suggesting a role for VEGF in the disease process. VEGF may have an important role in promoting glomerular repair in a variety of glomerular diseases.
Kanellis
John
J
Department of Nephrology, University of Melbourne, Australia.
Levidiotis
Vicki
V
Khong
Tiffany
T
Cox
Alison J
AJ
Stacker
Steven A
SA
Gilbert
Richard E
RE
Cooper
Mark E
ME
Power
David A
DA
D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology / Q000652:urine; D007150:Immunohistochemistry / Q000379:methods; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008297:Male; D009401:Nephrosis / Q000378:metabolism / Q000473:pathology / Q000652:urine; D011507:Proteinuria / Q000378:metabolism* / Q000473:pathology*; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis* / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000276:immunology
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D011692:Puromycin Aminonucleoside; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2