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.