CTGF expression in mesangial cells: involvement of SMADs, MAP kinase, and PKC

Kidney Int. 2002 Oct;62(4):1149-59. doi: 10.1111/j.1523-1755.2002.kid567.x.


Background: The induction of excess matrix in renal fibrosis seems to be mediated, at least in part, by the transforming growth factor-beta (TGF-beta)-mediated induction of connective tissue growth factor (CTGF) in mesangial cells.

Methods: By examining CTGF protein and mRNA expression and promoter activity in the presence or absence of TGF-beta or inhibitors, the signaling pathways controlling basal and TGF-beta-induced CTGF expression in mesangial cells were investigated.

Results: TGF-beta enhances CTGF mRNA and protein expression in mesangial cells. Mutation of a consensus SMAD binding element in the CTGF promoter completely abolished TGF-beta-induced CTGF expression and reduced basal CTGF expression. The previously identified basal control element-1 (BCE-1) site, but not Sp1 contributes to basal CTGF promoter activity. Ras/MEK/ERK, protein kinase C (PKC) and tyrosine kinase activity also contribute to basal and TGF-beta-induced CTGF promoter activity in cultured mesangial cells.

Conclusions: The TGF-beta-induction of CTGF in mesangial cells requires SMADs and PKC/ras/MEK/ERK pathways. SMADs are involved in basal CTGF expression, which presumably reflects the fact that mesangial cells express TGF-beta endogenously. TGF-beta also induces CTGF through ras/MEK/ERK. Inhibiting ras/MEK/ERK seems not to reduce phosphorylation (that is, activation) of SMADs, suggesting that SMADs, although necessary, are insufficient for the TGF-beta-stimulation of the CTGF promoter through ras/MEK/ERK. Thus, maximal TGF-beta induction of CTGF requires synergy between SMAD and ras/MEK/ERK signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Connective Tissue Growth Factor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / physiology*
  • Immediate-Early Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / genetics*
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Kinase C / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Response Elements
  • Smad Proteins
  • Sp1 Transcription Factor / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / pharmacology


  • CCN2 protein, rat
  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Smad Proteins
  • Sp1 Transcription Factor
  • Trans-Activators
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases