L-Arginine treatment may prevent tubulointerstitial nephropathy caused by germanium dioxide.
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)-beta1 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-beta1 protein and collagen type IV protein was markedly increased in the tubulointerstitium of the renal cortex from rats with GeO2-induced nephropathy. Similarly, TGF-beta1 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-beta1 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-beta1 mRNA and collagen type IV mRNA and protein in rats with GeO2-induced nephropathy.


CONCLUSIONS
In general, collagen synthesis is driven by TGF-beta1 in the fibrotic process associated with a variety of renal disorders. TGF-beta1 is secreted by TGF-beta1 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-beta1 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-beta1 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.
Yanagisawa
H
H
Department of Hygiene and Preventive Medicine, Faculty of Medicine, Saitama Medical School, Saitama, Japan. hiro@ns2.saitama-med.ac.jp
Yamazaki
N
N
Sato
G
G
Wada
O
O
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D005857:Germanium / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000187:drug effects*; D008264:Macrophages / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D005857:Germanium; C040516:germanium oxide; D003094:Collagen; D001120:Arginine