Impaired Angiogenesis in the Remnant Kidney Model: II. Vascular Endothelial Growth Factor Administration Reduces Renal Fibrosis and Stabilizes Renal Function

Abstract

Abstract.: Impaired angiogenesis and decreased vascular endothelial growth factor (VEGF) expression were recently documented in the remnant kidney (RK) model of progressive renal failure. VEGF (50 μg/kg, twice daily) was administered to RK rats between weeks 4 and 8 after surgery, and rats were euthanized at week 8 for histologic study. During the administration of VEGF (n = 7) or vehicle (n = 6), systemic BP was comparable in the two groups. VEGF treatment resulted in improved renal function and lower mortality rates, compared with the vehicle-treated group. Renal histologic analyses confirmed a 3.5-fold increase in glomerular endothelial cell proliferation (0.14 ± 0.03 versus 0.04 ± 0.02 proliferating endothelial cells/glomerulus, VEGF versus vehicle, P < 0.05), a twofold increase in peritubular capillary endothelial cell proliferation (1.60 ± 0.30 versus 0.78 ± 0.17 cells/mm 2, VEGF versus vehicle, P < 0.01), a threefold decrease in peritubular capillary rarefaction (P < 0.01), and a twofold increase in endothelial nitrix oxide synthase expression (P < 0.05) in the VEGF-treated group; an eightfold increase in urinary nitrate/nitrite levels (P < 0.05) was also noted. Although the difference in glomerulosclerosis scores did not reach statistical significance (0.67 ± 0.42 versus 1.22 ± 0.63, VEGF versus vehicle; range, 0 to 4; P = NS), VEGF-treated rats exhibited less interstitial collagen type III deposition (9.32 ± 3.26 versus 17.45 ± 7.50%, VEGF versus vehicle, P < 0.01) and reduced tubular epithelial cell injury, as manifested by osteopontin expression (5.57 ± 1.60 versus 9.58 ± 3.45%, VEGF versus vehicle, P < 0.01). In conclusion, VEGF treatment reduces fibrosis and stabilizes renal function in the RK model. The use of angiogenic factors may represent a new approach to the treatment of kidney disease.