DOCA and TGF-beta induce early growth response gene-1 (Egr-1) expression.
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.
Friedrich
Björn
B
Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.
Janessa
Andrea
A
Artunc
Ferruh
F
Aicher
Wilhelm Karl
WK
Müller
Gerhard Anton
GA
Lang
Florian
F
Risler
Teut
T
Alexander
Dorothea
D
D000818:Animals; D002460:Cell Line; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics; D051379:Mice; D012965:Sodium Chloride; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016212:Transforming Growth Factor beta; D003900:Desoxycorticosterone; D012965:Sodium Chloride