埼玉医科大学雑誌 第31巻 第1号 (2004年1月) 13-24頁 ◇論文(図表を含む全文)は，PDFファイルとなっています．
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アリストロキア酸中毒性腎症に対するHepatocyte Growth Factor (HGF)の線維化抑制作用の検討
Hepatocyte Growth Factor Attenuates Reactive Renal Fibrosis in Aristolochic Acid Nephrotoxicity
Yusuke Watanabe (Department of Nephrology, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan)
Despite the diverse initial causes, chronic renal disease that progress to end-stage renal failure is a remarkably monotonous process that is characterized by the relentless accumulation of extracellular matrix (ECM) leading to widespread interstitial fibrosis. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocyte, shows mitogenic, morphogenic and anti-apoptotic activities for a wide variety of cells including renal tubular epithelial cells. And HGF has been demonstrated to attenuate acute tubular necrosis and interstitial fibrosis in some of rodent models of kidney disease. But the mechanism of anti-fibrotic effects of HGF has been poorly understood in detail. Then, using HGF transgenic mice, we investigated how HGF could affect chronic toxic nephropathy/interstitial fibrosis caused by a nephrotoxin, aristrochic acid (AA). To find out molecular mechanisms of anti-fibrotic effects of HGF, cultured murine tubular epithelial cells (mProx24) were also employed. Significant tubular degeneration was observed both in the transgenic and the wild-type mice to the same degree after 2 week's treatment with AA. Interstitial fibrosis subsequently developed in the wild-type mice 4 weeks after cessation of AA administration. However, the transgenic mice manifested less fibrotic changes. Decreased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) could partially account for the attenuation of fibrogenesis in the transgenic mouse kidney. HGF at 10 ng/mL and 100 ng/mL could block TIMP-1 gene expression in mProx24 induced by epidermal growth factor (EGF), but a decrease in the number of mProx24 via apoptosis induced by AA was blocked only by HGF at 100 ng/mL.
In conclusion, circulating transgene-derived HGF (2〜10 ng/mL) could not prevent tubular degeneration caused by AA, but facilitate its regeneration without significant fibrogenesis. These findings suggest possible therapeutic efficacy for renal interstitial fibrosis following tubular degeneration even of low-dose HGF.
Keywords: hepatocyte growth factor (HGF), aristolochic acid (AA), renal interstitial fibrosis, tissue inhibitor of metalloproteinase-1 (TIMP-1), epidermal growth factor (EGF), type I collagen
J Saitama Med School 2004;31:13-24
(Received November 1, 2003)