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(American Journal of Pathology. 2001;158:1733-1741.)
© 2001 American Society for Investigative Pathology

Regular Articles

A Vitamin D Analog Ameliorates Glomerular Injury on Rat Glomerulonephritis

Kojiro Makibayashi^*, Mitsuyoshi Tatematsu, Michinori Hirata, Naoshi Fukushima, Kenichiro Kusano, Seiji Ohashi, Hideharu Abe, Kogo Kuze^*, Atsushi Fukatsu^*, Toru Kita and Toshio Doi

From the Division of Artificial Kidneys^*
and the Department of Geriatric Medicine,
Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto; the Chugai Pharmaceutical Company, Limited,
Shizuoka; and the Department of Laboratory Medicine,
School of Medicine, The University of Tokushima, Tokushima, Japan

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)₂D₃ 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)₂D₃-treated group showed higher levels. The disease control group showed a marked increase of type I and type IV collagens, and -smooth muscle actin (-SMA) compared to the normal group. The treatment of OCT or 1,25(OH)₂D₃ 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 -SMA at day 8 compared to normal rats. Treatment with OCT or 1,25(OH)₂D₃ inhibited the mRNA expressions of type I and type IV collagens, as well as that of -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-ß1 protein in the glomeruli, but treatment with OCT or 1,25(OH)₂D₃ 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-ß1. The present results suggest that OCT has potential for use in therapeutic strategy for the treatment of glomerulonephritis without inducing hypercalcemia.

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