Nephrol Dial Transplant (2003) 18: 2515-2523
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Transgene-derived hepatocyte growth factor attenuates reactive renal fibrosis in aristolochic acid nephrotoxicity
1Department of Nephrology, Saitama Medical College, Irumagun, 2Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, 3Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Medical School, Suita and 4Center of Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Japan
Correspondence and offprint requests to: Hiromichi Suzuki, MD, PhD, Department of Nephrology, Saitama Medical College, 38 Morohongo, Moroyama-machi, Irumagun, Saitama 350-0495, Japan. Email: iromichi{at}saitama-med.ac.jp
Background. Hepatocyte growth factor (HGF) has been demonstrated to attenuate acute tubular necrosis and interstitial fibrosis in a variety of rodent models of kidney disease. We investigated how HGF could affect chronic toxic nephropathy/interstitial fibrosis caused by aristolochic acid (AA).
Methods. Wild-type and HGF transgenic mice received daily intraperitoneal injections of AA for 14 days. At sacrifice, kidneys were removed and used for microscopy examination and in vitro studies. To determine the molecular mechanisms of anti-fibrotic effects of HGF, cultured murine tubular epithelial cells (mProx24) were employed.
Results. Significant tubular degeneration was observed in both the transgenic and the wild-type mice to the same degree after 2 weeks 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) and increased matrix metalloproteinase-9 activity could partially account for the attenuation of fibrogenesis in the transgenic mouse kidney. HGF at 10 and 100 ng/ml could block TIMP-1 gene expression in mProx24 induced by epidermal growth factor, but a decrease in the number of mProx24 via apoptosis induced by AA was blocked only by HGF at 100 ng/ml.
Conclusion. Circulating transgene-derived HGF (2–10 ng/ml) could not prevent tubular degeneration caused by AA, but attenuated interstitial fibrogenesis during tubular regeneration. These findings suggest a possible therapeutic efficacy for renal interstitial fibrosis following tubular degeneration even of low-dose HGF.
Keywords: aristolochic acid; hepatocyte growth factor; matrix metalloproteinase-9; renal fibrosis; tissue inhibitor of metalloproteinase-1
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