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

Background. Long-term oral ingestion of germanium dioxide (GeO2) causes pro gressive renal failure derived from tubulointerstitial nephropathy in human s and animals. The characteristic of GeO2-induced nephropathy is the renal tissue injury persisting for a long time, even after cessation of GeO2 inge stion. 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 transcriptio n-polymerase chain reaction, we examined the expression of ED1-positive cel ls (macrophages/monocytes), transforming growth factor (TGF)-beta(1) mRNA a nd protein and collagen type IV mRNA and protein in the kidneys of rats wit h GeO2-induced nephropathy. Concomitantly, the effects of L-arginine treatm ent on their expression was explored in the kidneys of rats with GeO2-induc ed nephropathy. Results. Chronic administration of GeO2 caused tubulointerstitial nephropat hy characterized by leukocyte invasion into the enlarged tubulointerstitial space in rats. The expression of ED1-positive cells, TGF-PI protein and co llagen type IV protein was markedly increased in the tubulointerstitium of the renal cortex from rats with GeO2-induced nephropathy. Similarly, TGF-be ta(1) and collagen type IV mRNA were significantly enhanced in the renal co rtex of rats with GeO2-induced nephropathy. A small number of tubulointerst itial cells expressing TGF-beta(1) 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-be ta(1) mRNA and collagen type IV mRNA and protein in rats with GeO2-induced nephropathy. Conclusions. In general, collagen synthesis is driven by TGF-beta(1) in the fibrotic process associated with a variety of renal disorders. TGF-beta(1) is secreted by TGF-beta(1) producing cells such as macrophages, fibroblast s and myofibroblasts. Thus, the present study indicates that the expression of collagen type IV may be mediated by TGF-beta(1) 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 suppr essing macrophage invasion and the resultant TGF-beta(1) expression in this nephropathy. L-Arginine treatment may be beneficial in the prevention of t ubulointerstitial fibrosis, which is considered to be the terminal stage of GeO2-induced nephropathy.