Inhibitory effects of L-arginine treatment on the progression of GeO₂-induced tubulointerstitial nephropathy

抄録

Long-term oral ingestion of germanium dioxide ( GeO₂) causes progressive renal failure derived from tubulointerstitial nephropathy in humans. The characteristic of GeO₂-induced nephropathy is the renal tissue injury persisting for a long time even after cessation of GeO₂ ingestion. To elucidate the mechanisms involved, we examined the expression of ED₁-positive cells (macrophages/monocytes), transforming growth factor (TGF)-β₁ and collagen type IV in the kidneys of rats with GeO₂-induced nephropathy. Concomitantly, we explored the effect of L-arginine treatment on their expression in the kidneys of rats with GeO₂-induced nephropathy. Chronic administration of GeO₂ caused tubulointerstitial nephropathy characterized by leukocyte invasion into the enlarged tubulointerstitial space in rats. The expression of ED₁-positive cells, TGF-β₁ and collagen type IV was markedly increased in the tubulointerstitium of the renal cortex from rats with GeO₂-induced nephropathy. However, L-arginine treatment led to a parallel decrease in the expression of ED₁-positivecells, TGF-β₁ and collagen type IV in rats with GeO₂-induced nephropathy. In general, collagen synthesis is driven by TGF-β₁ in the fibrotic process associated with a variety of renal disorders. TGF-β₁ is secreted by TGF-β₁ producing cells such as macrophages. Thus, the present study indicates that the expression of collagen type IV may be mediated by TGF-β₁ released from invading macrophages. L-Arginine treatment inhibits collagen type IV synthesis possibly by suppressing macrophage invasion and the resultant TGF-β₁ expression in this nephropathy. L-Arginine treatment may be beneficial in the prevention of tubulointerstitial fibrosis which is considered to be the terminal stage of GeO₂-induced nephropathy.