L-Arginine treatment may prevent tubulointerstitial nephropathy caused by germanium dioxide

Abstract

Background. Long-term oral ingestion of germanium dioxide (GeO2) causes progressive renal failure derived from tubulointerstitial nephropathy in humans and animals. The characteristic of GeO2-induced nephropathy is the renal tissue injury persisting for a long time, even after cessation of GeO2 ingestion. However, a treatment that can suppress the long-lasting renal tissue injury has not yet been established. Methods. Using the methods of immunohistochemistry and reverse transcription-polymerase chain reaction, we examined the expression of ED1-positive cells (macrophages/monocytes), transforming growth factor (TGF)-β1 mRNA and protein and collagen type IV mRNA and protein in the kidneys of rats with GeO2-induced nephropathy. Concomitantly, the effects of L-arginine treatment on their expression was explored in the kidneys of rats with GeO2-induced nephropathy. Results. 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 protein and collagen type IV protein was markedly increased in the tubulointerstitium of the renal cortex from rats with GeO2-induced nephropathy. Similarly, TGF- β1 and collagen type IV mRNA were significantly enhanced in the renal cortex of rats with GeO2-induced nephropathy. A small number of tubulointerstitial cells expressing TGF-β1 protein were also observed in the renal cortex of rats with GeO2-induced nephropathy. However, L-arginine treatment led to a parallel decrease in the expression of ED1-positive cells, TGF-β1 mRNA and collagen type IV mRNA and protein in rats with GeO2- induced nephropathy. Conclusions. 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, fibroblasts and myofibroblasts. Thus, the present study indicates that the expression of collagen type IV may be mediated by TGF-β1 released from invading macrophages and, to a lesser extent, released from tubulointerstitial cells, presumably fibroblasts and/or myofibroblasts in GeO2-induced nephropathy. 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.