Clinical evidence links the inhibition of vascular endothelial growth factor (VEGF) to hypertension. However, the mechanisms by which VEGF affects the pathogenesis of hypertension remain in question. We determined: 1) whether administration of VEGF receptor inhibitor (SU5416) enhances dietary salt-induced hypertension in SD rats; and 2) whether VEGF or SU5416 directly affects proliferation of cultured human renal proximal tubular epithelial cells (HRPTEC) and eNOS expression in cultured human glomerular microvassel endothelial cells (HGMEC). Ten 10 wk old male SD rats received a high sodium diet (HS, 8%) and the other ten SD rats received a normal sodium diet (NS, 0.5 %) for 4 wks. After 2 wks of the dietary program, five rats were administered with SU5416 at 10 mg/kg/d, i.p. or DMSO (vehicle) for 14 days in HS and NS groups. MAP was significantly higher in rats treated with SU5416, as opposed to those treated with DMSO and fed with HS for 4 wks (157.6±3.9 vs. 125.9±4.3 mmHg, P<0.01). Increased proteinuria and albuminuria were associated with marked renal histological abnormalities in HS group with SU5416 administration, compared with those in the vehicle HS group. 3H-thymidine incorporation assay showed that SU5416 blocked the actions of both exogenous and endogenous VEGF on the proliferation of HRPTEC. VEGF (10 ng/ml) significantly increased eNOS protein levels by 29% in cultured HGMEC, but its action was completely abolished by SU5416. These results suggest that VEGF receptor inhibition enhances dietary salt-induced hypertension and kidney injury, possibly by direct damage on renal cells and decreasing NO production by eNOS.