A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis.
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.
Makibayashi
K
K
Division of Artificial Kidneys and the Department of Geriatric Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Tatematsu
M
M
Hirata
M
M
Fukushima
N
N
Kusano
K
K
Ohashi
S
S
Abe
H
H
Kuze
K
K
Fukatsu
A
A
Kita
T
T
Doi
T
T
D000199:Actins / Q000032:analysis / Q000235:genetics; D000419:Albuminuria / Q000652:urine; D000818:Animals; D001806:Blood Urea Nitrogen; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D003094:Collagen / Q000032:analysis / Q000235:genetics; D003404:Creatinine / Q000097:blood; D015870:Gene Expression; D005921:Glomerulonephritis / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000737:chemistry; D010710:Phosphates / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000199:Actins; D010710:Phosphates; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D003404:Creatinine; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium