The alpha 1 beta 1
integrin (VLA-1) is a major
collagen/
laminin receptor that regulates fibroblast proliferation and mesangial cell migration and cell contraction. We have examined the effect of an antibody to
VLA-1 in crescentic
glomerulonephritis. Nephrotoxic
nephritis was induced in Wistar-Kyoto rats and rats were given
monoclonal antibody to
VLA-1 (Ha31/8), 2.5 mg/kg, on alternate days.
Antibodies were given from day -1 to day 10 or from day 14 to day 28. Treatment from day -1 to day 10, during the early inflammatory phase of nephrotoxic
nephritis, had no effect on
albuminuria or glomerular crescent formation. In the
delayed treatment experiment, all rats developed florid crescentic
glomerulonephritis, and control rats showed marked glomerular and tubulointerstitial
scarring at day 32.
VLA-1 expression, by immunohistochemistry, was increased in glomeruli and around tubules.
Proteinuria did not differ between groups. In anti-VLA-1-treated rats, serum
creatinine was significantly lower at day 32 (P = 0.002) and renal survival was significantly better (P = 0.045). Both glomerular and interstitial
scarring were significantly less at day 32 in rats given anti-VLA-1 (P = 0.002). Deposition of ED(A)
fibronectin, a marker of new matrix synthesis, and of
type IV collagen, were reduced in glomeruli and interstitium in anti-VLA-1-treated animals (P = 0.0006). Expression of alpha-smooth muscle actin, a marker of myofibroblasts, showed no significant difference. Expression of
matrix metalloproteinase-9 was increased in the glomeruli of rats treated with anti-VLA-1. We conclude that
VLA-1 mediates both glomerular and interstitial
fibrosis in crescentic
glomerulonephritis and that neutralization of
VLA-1, which enhanced expression of
matrix metalloproteinase-9, is a possible therapeutic strategy in progressive renal
scarring.