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引起的进行性肾衰竭。据推测，其成因物质是GeO^2。我们在目前的研究中发现，长期给予GeO^2可诱导大鼠和人类的间质性肾炎，其特征为肾小管细胞变性和坏死、间质间隙扩大和白细胞侵入。免疫组织化学研究显示，在GeO^2诱导的肾病肾小球中，ED_1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）的表达显著增加。此外，FBNmRNA在GeO^2诱导的肾病中显著增加。L-精氨酸处理显著降低了细胞、蛋白和mRNA的表达，而ACE抑制剂依那普利对其无影响。近年来有研究表明巨噬细胞参与了CCL IV和FBN的积聚，因此，我们的结论是：（1）长期给予GeO^2不仅在人而且在大鼠中引起间质性肾炎：（2）在GeO^2诱导的肾病中，浸润的ED_1阳性细胞，尤其是巨噬细胞可能参与了驱动COL IV和FBN在肾小球中表达的过程;（3）L-精氨酸治疗通过阻断ED^1阳性细胞的侵袭以及COL IV和FBN的表达来阻止GeO^22诱导的肾病的进展。血管紧张素II似乎在这种肾病的进展中不起中心作用。

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.