Yanagisawa H, Yamazaki N, Sato G, Wada O
Department of Hygiene and Preventive Medicine, Faculty of Medicine, Saitama Medical School, Saitama, Japan.
Kidney Int. 2000 Jun;57(6):2275-84. doi: 10.1046/j.1523-1755.2000.00088.x.
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.
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.
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.
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.
长期口服二氧化锗（GeO2）会导致人和动物因肾小管间质性肾病而出现进行性肾衰竭。GeO2诱导的肾病的特征是即使在停止摄入GeO2后，肾组织损伤仍会持续很长时间。然而，尚未建立一种能够抑制这种长期肾组织损伤的治疗方法。
我们采用免疫组织化学和逆转录-聚合酶链反应方法，检测了GeO2诱导的肾病大鼠肾脏中ED1阳性细胞（巨噬细胞/单核细胞）、转化生长因子（TGF）-β1 mRNA和蛋白以及IV型胶原mRNA和蛋白的表达。同时，在GeO2诱导的肾病大鼠肾脏中探讨了L-精氨酸治疗对其表达的影响。
长期给予GeO2导致大鼠出现肾小管间质性肾病，其特征为白细胞侵入扩大的肾小管间质空间。在GeO2诱导的肾病大鼠肾皮质的肾小管间质中，ED1阳性细胞、TGF-β1蛋白和IV型胶原蛋白的表达显著增加。同样，在GeO2诱导的肾病大鼠肾皮质中，TGF-β1和IV型胶原mRNA也显著增强。在GeO2诱导的肾病大鼠肾皮质中也观察到少数表达TGF-β1蛋白的肾小管间质细胞。然而，L-精氨酸治疗导致GeO2诱导的肾病大鼠中ED1阳性细胞、TGF-β1 mRNA和IV型胶原mRNA及蛋白的表达平行下降。
一般来说，在与多种肾脏疾病相关的纤维化过程中，胶原合成由TGF-β1驱动。TGF-β1由巨噬细胞、成纤维细胞和肌成纤维细胞等TGF-β1产生细胞分泌。因此，本研究表明，IV型胶原的表达可能由侵入的巨噬细胞释放的TGF-β1介导，在较小程度上也由肾小管间质细胞（可能是成纤维细胞和/或肌成纤维细胞）释放的TGF-β1介导，这在GeO2诱导的肾病中。L-精氨酸治疗可能通过抑制巨噬细胞侵入以及由此导致的该肾病中TGF-β1的表达来抑制IV型胶原的合成。L-精氨酸治疗可能有助于预防肾小管间质纤维化，而肾小管间质纤维化被认为是GeO2诱导的肾病的终末期。
