title: Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function.
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 microg/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.
authors: Division of Nephrology, University of Washington, Seattle, Washington.
authors: Duk-Hee
authors: DH
authors: Kang
authors: Division of Nephrology, University of Washington, Seattle, Washington.
authors: Jeremy
authors: J
authors: Hughes
authors: Division of Nephrology, University of Washington, Seattle, Washington.
authors: Marilda
authors: M
authors: Mazzali
authors: Scios, Inc., Sunnyvale, California.
authors: George F
authors: GF
authors: Schreiner
authors: Division of Nephrology, University of Washington, Seattle, Washington.
authors: Richard J
authors: RJ
authors: Johnson
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D007674:Kidney Diseases / Q000401:mortality / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000098:blood supply; D007684:Kidney Tubules / Q000098:blood supply; D008222:Lymphokines / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D018919:Neovascularization, Physiologic; D009392:Nephrectomy; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D009573:Nitrites; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019001:Nitric Oxide Synthase