OCT (22-oxa-calcitriol), a
vitamin D analog, has been reported to show strong inhibitory effects on mesangial cell proliferation in vitro. In the present study, we report a study of the effect of OCT on
anti-thy-1 glomerulonephritis. Both OCT and
1,25(OH)(2)D(3) significantly inhibited mesangial cell proliferation, the degree of glomerulosclerosis, and
albuminuria at day 8 compared to the disease control group. The OCT-treated group showed normal
calcium levels but the 1,25(OH)(2)D(3)-treated group showed higher levels. The disease control group showed a marked increase of type I and type IV
collagens, and alpha-smooth muscle actin (alpha-SMA) compared to the normal group. The treatment of OCT or
1,25(OH)(2)D(3) significantly reduced the expression of these
proteins. The
mRNA of the glomeruli of
anti-thy-1 model expressed significantly higher levels of type I and type IV
collagens, and alpha-SMA at day 8 compared to normal rats. Treatment with OCT or
1,25(OH)(2)D(3) inhibited the
mRNA expressions of type I and type IV
collagens, as well as that of alpha-SMA. These data demonstrate that OCT inhibits mesangial cell proliferation and extracellular matrix expansion with a low calcemic activity. Disease control rats showed significantly increased levels of
transforming growth factor-beta1 protein in the glomeruli, but treatment with OCT or
1,25(OH)(2)D(3) markedly reduced this expression. The levels of
mRNA in glomeruli were also consistent with these
protein levels. Therefore, the suppressive effect of OCT may be mediated by inhibition of
transforming growth factor-beta1. The present results suggest that OCT has potential for use in therapeutic strategy for the treatment of
glomerulonephritis without inducing
hypercalcemia.