Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice.

Tsutomu Inoue, Hirokazu Okada, Tatsuya Kobayashi, Yusuke Watanabe, Yoshihiko Kanno, Jeffrey B. Kopp, Takashi Nishida, Masaharu Takigawa, Munehisa Ueno, Toshikazu Nakamura, Hiromichi Suzuki

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Abstract

We investigated the mechanism of the anti-fibrotic effects of hepatocyte growth factor (HGF) in the kidney, with respect to its effect on connective tissue growth factor (CTGF), a down-stream, profibrotic mediator of transforming growth factor-beta1 (TGF-beta1). In wild-type (WT) mice with 5/6 nephrectomy (Nx), HGF and TGF-beta1 mRNAs increased transiently in the remnant kidney by week 1 after the Nx, returned to baseline levels, and increased again at weeks 4 to 12. In contrast, CTGF and alpha1(I) procollagen (COLI) mRNAs increased in parallel with HGF and TGF-beta1 during the early stage, but did not re-increase during the late stage. In the case of TGF-beta1 transgenic (TG) mice with 5/6 Nx, excess TGF-beta1 derived from the transgene enhanced CTGF expression significantly in the remnant kidney, accordingly accelerating renal fibrogenesis. Administration of dHGF (5.0 mg/kg/day) to TG mice with 5/6 Nx for 4 weeks from weeks 2 to 6 suppressed CTGF expression in the remnant kidney, attenuating renal fibrosis and improving the survival rate. In an experiment in vitro, renal tubulointerstitial fibroblasts (TFB) were co-cultured with proximal tubular epithelial cells (PTEC). Pretreatment with HGF reduced significantly CTGF induction in PTEC by TGF-beta1, consequently suppressing COLI synthesis in TFB. In conclusion, HGF can block, at least partially, renal fibrogenesis promoted by TGF-beta1 in the remnant kidney, via attenuation of CTGF induction.

Original languageEnglish
Pages (from-to)268-270
Number of pages3
JournalFASEB Journal
Volume17
Issue number2
Publication statusPublished - 2003

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Connective Tissue Growth Factor
Transforming Growth Factor beta1
Hepatocyte Growth Factor
Kidney
Fibroblasts
Transgenic Mice
Messenger RNA
Epithelial Cells
Nephrectomy
Transgenes
Fibrosis

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Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice. / Inoue, Tsutomu; Okada, Hirokazu; Kobayashi, Tatsuya; Watanabe, Yusuke; Kanno, Yoshihiko; Kopp, Jeffrey B.; Nishida, Takashi; Takigawa, Masaharu; Ueno, Munehisa; Nakamura, Toshikazu; Suzuki, Hiromichi.

In: FASEB Journal, Vol. 17, No. 2, 2003, p. 268-270.

Research output: Contribution to journalArticle

Inoue, Tsutomu ; Okada, Hirokazu ; Kobayashi, Tatsuya ; Watanabe, Yusuke ; Kanno, Yoshihiko ; Kopp, Jeffrey B. ; Nishida, Takashi ; Takigawa, Masaharu ; Ueno, Munehisa ; Nakamura, Toshikazu ; Suzuki, Hiromichi. / Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice. In: FASEB Journal. 2003 ; Vol. 17, No. 2. pp. 268-270.
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AU - Inoue, Tsutomu

AU - Okada, Hirokazu

AU - Kobayashi, Tatsuya

AU - Watanabe, Yusuke

AU - Kanno, Yoshihiko

AU - Kopp, Jeffrey B.

AU - Nishida, Takashi

AU - Takigawa, Masaharu

AU - Ueno, Munehisa

AU - Nakamura, Toshikazu

AU - Suzuki, Hiromichi

PY - 2003

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