Transgene-derived hepatocyte growth factor attenuates reactive renal fibrosis in aristolochic acid nephrotoxicity.
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.


CONCLUSIONS
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.
Okada
Hirokazu
H
Department of Nephrology, Saitama Medical College, 30 Morohongo, Moroyama-machi, Irumagun, Saitama 350-0495, Japan.
Watanabe
Yusuke
Y
Inoue
Tsutomu
T
Kobayashi
Tatsuya
T
Kanno
Yoshihiko
Y
Shiota
Goshi
G
Nakamura
Toshikazu
T
Sugaya
Takeshi
T
Fukamizu
Akiyoshi
A
Suzuki
Hiromichi
H
D000818:Animals; D034341:Aristolochic Acids / Q000009:adverse effects*; D005355:Fibrosis; D006133:Growth Substances / Q000235:genetics / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D023421:Models, Animal; D009676:Noxae / Q000009:adverse effects*; D019076:Transgenes / Q000235:genetics
D034341:Aristolochic Acids; D006133:Growth Substances; D009676:Noxae; D017228:Hepatocyte Growth Factor; C000228:aristolochic acid I