Mechanisms responsible for the progression of GeO_2-induced nephropathy

众所周知，长期口服含锗化合物会导致人类间质性肾炎所致的进行性肾功能衰竭。本研究发现，慢性给予Geo^2可引起大鼠和人肾小管上皮细胞变性、坏死、间质增厚和白细胞侵入等间质性肾炎。免疫组织化学显示肾间质中ED1阳性细胞(巨噬细胞和单核细胞)、IV型胶原(Col IV)和纤维连接蛋白(FBN)表达明显增加。此外，在GeO^2诱导的肾病模型中，FBNmRNA的表达显著增加。L-精氨酸处理显著降低细胞、蛋白质和mRNA的表达，而血管紧张素转换酶抑制剂依那普利对其无影响。最近有报道称，巨噬细胞参与了Col IV和FBN的积聚，因此，我们的结论如下：(L)长期服用Geo^2可引起大鼠和人的间质性肾炎；(2)ED_1阳性细胞，特别是巨噬细胞可能参与了推动Col IV和FBN在Geo^2肾病间质中的表达；(3)L精氨酸治疗通过阻断ED^1阳性细胞的入侵而阻止Geo^22诱导的肾病的进展，而Col IV和FBN的表达似乎不在此肾病的进展过程中起中心作用。

It is known that longstanding oral ingestion of Ge-containing compounds causes progressive renal failure derived from interstitial nephritis in humans. The causative substance is supposed to be GeO^2. We found in the present study that chronic administration of GeO^2 induced interstitial nephritis characterized by tubular cell degeneration and necrosis, enlarged interstitial space and invading leukocytes in rats as well as in humans. Immunohistochemical studies revealed markedly increased expression of ED_1-positive cells (macrophages and monocytes), collagen type IV(COL IV) and fibronectin(FBN) in the interstitium of GeO^2-induced nephropathy. Also, FBNmRNA was significantly increased in GeO^2-induced nephropathy. L-Arginine treatment substantially decreased the increased expression of their cells, proteins and mRNA.The ACE inhibitor enalapril, however, had no effects on them. It is recently reported that macrophages are involved in the accumulation of CCL IV and FBN.Thus, our conclusion is as follows ; (l)long-term administration of GeO^2 causes interstitial nephritis not only in humans but also in rats ; (2)Infiltrating ED_1-positive cells, especially macrophages presumably participate in driving the expression of COL IV and FBN in the interstitium of GeO^2-induced nephropathy ; (3) L-arginine treatment prevents the progression of GeO^22-induced nephropathy by blocking the invasion of ED^1-positive cells and the expression of COL IV and FBN.Angiotensin II does not appear to play a central role in the progression of this nephropathy.