A Vitamin D Analog Ameliorates Glomerular Injury on Rat Glomerulonephritis

Abstract

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 OCTtreated 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 ␣-smooth muscle actin (␣-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 ␣-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 ␣-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-␤1 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-␤1. The present results suggest that OCT has potential for use in therapeutic strategy for the treatment of glomerulonephritis without inducing hypercalcemia. (Am J Pathol 2001, 158:1733-1741) A number of progressive glomerular diseases are characterized by initial mesangial cell proliferation, which is followed by glomerulosclerosis, and finally develops to end-stage kidney disease. Examples of this process are membranoproliferative glomerulonephritis, diabetic nephropathy, and IgA nephropathy.1,2 Nonanticoagulant heparin, a potent in vitro inhibitor of mesangial cell proliferation, inhibits mesangial cell proliferation and matrix expansion in mesangioproliferative glomerulonephritis. 3Treatment with anti-platelet-derived growth factor also blocks mesangial cell proliferation in vivo, preventing the development of glomerulosclerosis. 4 This suggests that mesangial cell proliferation may play an important role in the development of glomerular lesions. Therefore, the search for agents capable of inhibiting mesangial cell proliferation is clinically important for progressive glomerular change.Recently, 1,25(OH) 2 D 3 was shown to have a preventive effect in progressive glomerular damage in a renal ablation model. 5 However, 1,25(OH) 2 D 3 has an adverse effect in that its use leads to hypercalcemia and hyperphosphatemia, which eventually represent risk factors for the progression of renal injury. It is, therefore, difficult to use 1,25(OH) 2 D 3 for the practical treatment of patie...

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