Post-cyclosporine-mediated hypertension and nephropathy: amelioration by vascular endothelial growth factor

Recent studies have demonstrated a role for microvascular and tubulointerst itial injury in some models of salt- sensitive hypertension. We utilized a model of post- cyclosporin A (CsA) nephropathy and hypertension to test the hypothesis that treatment with an angiogenic factor aimed at ameliorating the microvascular and renal injury would prevent the development of hyperte nsion. CsA was administered with a low- salt diet for 45 days, resulting in a renal lesion characterized by afferent arteriolopathy, focal peritubular capillary loss, and tubulointerstitial fibrosis. Rats were then placed on a high- salt diet and randomized to receive either vascular endothelial gro wth factor (VEGF(121))or vehicle for 14 days. Placement of rats with establ ished CsA nephropathy on a high- salt diet results in the rapid development of salt- sensitive hypertension. VEGF(121) treatment resulted in lower blo od pressure, and this persisted on discontinuing the VEGF. VEGF(121) treatm ent was also associated with a decrease in osteopontin expression, macropha ge infiltration, and collagen III deposition and markedly stimulated resolu tion of the arteriolopathy (20.9 +/- 7.8 vs. 36.9 +/- 6.1%, VEGF vs. vehicl e, P < 0.05). In conclusion, CsA- associated renal microvascular and tubulo interstitial injury results in the development of salt- sensitive hypertens ion. Treatment of animals with established CsA nephropathy with VEGF reduce s the hypertensive response and accelerates histological recovery. The vasc ular protective effect of VEGF may be due to the improvement of arteriolopa thy. Angiogenic growth factors may represent a novel strategy for treating CsA- associated hypertension and renal disease.