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

FASEB J. 2003 Feb;17(2):268-70. doi: 10.1096/fj.02-0442fje. Epub 2002 Dec 3.

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.

MeSH terms

  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Connective Tissue Growth Factor
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fibrosis
  • Gene Expression
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Hepatocyte Growth Factor / pharmacology
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney / surgery
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Nephrectomy
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1

Substances

  • CCN2 protein, mouse
  • Collagen Type I
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Hepatocyte Growth Factor