Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis.
Vascular endothelial growth factor (VEGF) regulates angiogenesis through endothelial cell proliferation and plays an important role in capillary repair in damaged glomeruli. We tested the hypothesis that VEGF might be beneficial in rats with severe glomerular injury in glomerulonephritis (GN) based on its angiogenic and vascular remodeling properties. Acute GN with severe glomerular destruction was induced in rats by injection of anti-Thy-1.1 antibody (day 0) and Habu-snake venom (day 1). Rats were intraperitoneally injected with recombinant human VEGF(165) (10 microg/100 g body wt/day) or vehicle from day 2 to day 9, and monitored changes in glomerular capillaries, development of glomerular inflammation, and progression to glomerular sclerosis after acute glomerular destruction in both groups. Rats that received anti-Thy-1.1 antibody and Habu-snake venom showed severe mesangiolysis and marked destruction of capillary network on day 2. VEGF was expressed on glomerular epithelial cells, proliferating mesangial cells, and some infiltrating leukocytes, and VEGF(165) protein levels increased in damaged glomeruli during day 5 to day 7. Normal, damaged, and regenerating glomerular endothelial cells expressed VEGF receptor flk-1. However, endothelial cell proliferation and capillary repair was rare in vehicle-treated rats with severe glomerular damage, which progressed to global sclerosis and chronic renal failure by week 8. In contrast, in the VEGF-treated group, VEGF(165) significantly enhanced endothelial cell proliferation and capillary repair in glomeruli by day 9 (proliferating endothelial cells: VEGF(165), 4.3 +/- 1.1; control, 2.2 +/- 0.9 cells on day 7, P < 0.001; and glomerular capillaries: VEGF(165), 24.6 +/- 4.8; control, 16.9 +/- 3.4 capillaries on day 7, P < 0.01). Thereafter, damaged glomeruli gradually recovered after development of capillary network by week 8, and significant improvement of renal function was evident in the VEGF-treated group during week 8 (creatinine: VEGF(165), 0.3 +/- 0.1; control, 2.6 +/- 0.9 mg/dl, P < 0.001; proteinuria: VEGF(165), 54 +/- 15; control, 318 +/- 60 mg/day, P < 0.001). We conclude that the beneficial effect of VEGF(165) in severe glomerular injury in GN emphasizes the importance of capillary repair in the resolution of GN, and may allow the design of new therapeutic strategies against severe GN.
Masuda
Y
Y
Department of Pathology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Shimizu
A
A
Mori
T
T
Ishiwata
T
T
Kitamura
H
H
Ohashi
R
R
Ishizaki
M
M
Asano
G
G
Sugisaki
Y
Y
Yamanaka
N
N
D000818:Animals; D000911:Antibodies, Monoclonal; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000032:analysis; D003435:Crotalid Venoms; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005921:Glomerulonephritis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007518:Isoantibodies; D007678:Kidney Glomerulus / Q000098:blood supply*; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D011507:Proteinuria; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000032:analysis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D018800:Thy-1 Antigens; D017841:Trimeresurus; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D003435:Crotalid Venoms; D016228:Endothelial Growth Factors; D007518:Isoantibodies; D008222:Lymphokines; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D018800:Thy-1 Antigens; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C035678:anti-Thy antibody; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor