DOCA and TGF-beta induce early growth response gene-1 (Egr-1) expression

Cell Physiol Biochem. 2008;22(5-6):465-74. doi: 10.1159/000185495. Epub 2008 Dec 9.


Renal fibrosis is characterized by excessive accumulation of extracellular matrix proteins. Recent findings show that transforming growth factor-beta (TGF-beta) induces a rapid but transient expression of early growth response gene-1 (Egr-1) by skin fibroblasts. The present study aims to define the role of Egr-1 in mineralocorticoid-induced renal fibrosis. Therefore, we transiently transfected immortalized human renal fibroblasts (TK188) with recombinant Egr-1 and analysed the transcription of several pro-fibrotic genes (Coll1A1, Coll1A2, osteopontin, TIMP-1, and CTGF). We also examined Egr-1 expression and the regulation of pro-fibrotic genes in DOCA- (deoxycorticosterone acetate) and TGF-beta-treated renal fibroblasts. Finally, we compared Egr-1 gene expression in DOCA/high salt-induced fibrotic kidneys and untreated mice. Egr-1 transfection of TK188 fibroblasts induced the expression of TIMP-1 and osteopontin mRNA. Similar results were obtained after DOCA-activation of TK188 cells. Stimulation of TK188 with TGF-beta, but not with DOCA, resulted in elevated Coll1A1/Coll1A2 and CTGF levels. Co-stimulation with DOCA and TGF-beta was followed by enhanced Egr-1, Coll1A1, TIMP-1, and CTGF transcription. In conclusion, both DOCA and TGF-beta alone or in combination synergistically induced Egr-1 expression by human renal fibroblasts. DOCA induction of TIMP-1/osteopontin is Egr-1 dependent, whereas TGF-beta appears to induce Coll1A1 and CTGF by an Egr-1 independent pathway. In vivo analyses revealed significantly higher Egr-1 transcript levels in DOCA/high salt-induced fibrotic kidneys compared to untreated mice. Thus, we show for the first time that Egr-1 might participate in DOCA-induced renal fibrosis.

MeSH terms

  • Animals
  • Cell Line
  • Desoxycorticosterone / analogs & derivatives*
  • Desoxycorticosterone / pharmacology
  • Disease Models, Animal
  • Early Growth Response Protein 1 / genetics*
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Humans
  • Kidney Diseases / genetics
  • Mice
  • Sodium Chloride
  • Time Factors
  • Transfection
  • Transforming Growth Factor beta / pharmacology*


  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Transforming Growth Factor beta
  • Desoxycorticosterone
  • Sodium Chloride