Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions.
Inhibiting the actions of VEGF is a new therapeutic paradigm in cancer management with antiangiogenic therapy also under intensive investigation in a range of nonmalignant diseases characterized by pathological angiogenesis. However, the effects of VEGF inhibition on organs that constitutively express it in adulthood, such as the kidney, are mostly unknown. Accordingly, we examined the effect of VEGF inhibition on renal structure and function under physiological conditions and in the setting of the common renal stressors: hypertension and activation of the renin-angiotensin system. When compared with normotensive Sprague-Dawley (SD) rats, glomerular VEGF mRNA was increased 2-fold in transgenic (mRen-2)27 rats that overexpress renin with spontaneously hypertensive rat (SHR) kidneys showing VEGF expression levels that were intermediate between them. Administration of either an orally active inhibitor of the type 2 VEGF receptor (VEGFR-2) tyrosine kinase or a VEGF neutralizing antibody to TGR(mRen-2)27 rats resulted in loss of glomerular endothelial cells and transformation to a malignant hypertensive phenotype with severe glomerulosclerosis. VEGFR-2 kinase inhibition treatment was well tolerated in SDs and SHRs; although even in these animals there was detectable endothelial cell loss and rise in albuminuria. Mild mesangial expansion was also noted in hypertensive SHR, but not in SD rats. These studies illustrate: (i) VEGF has a role in the maintenance of glomerular endothelial integrity under physiological circumstances, (ii) glomerular VEGF is increased in response to hypertension and activation of the renin-angiotensin system, and (iii) VEGF signaling plays a protective role in the setting of these renal stressors.
Advani
Andrew
A
Department of Medicine, University of Toronto, St. Michael's Hospital, Toronto, ON, Canada M5C 2T2.
Kelly
Darren J
DJ
Advani
Suzanne L
SL
Cox
Alison J
AJ
Thai
Kerri
K
Zhang
Yuan
Y
White
Kathryn E
KE
Gow
Renae M
RM
Marshall
Sally M
SM
Steer
Brent M
BM
Marsden
Philip A
PA
Rakoczy
P Elizabeth
PE
Gilbert
Richard E
RE
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006262:Health; D006801:Humans; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000906:Antibodies; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib