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DOCA and TGF-beta induce early growth response gene-1 (Egr-1) expression. 2008

Björn Friedrich, and Andrea Janessa, and Ferruh Artunc, and Wilhelm Karl Aicher, and Gerhard Anton Müller, and Florian Lang, and Teut Risler, and Dorothea Alexander
Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.

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.

UI MeSH Term Description Entries
D007674 Kidney Diseases Pathological processes of the KIDNEY or its component tissues. Disease, Kidney,Diseases, Kidney,Kidney Disease
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D003900 Desoxycorticosterone A steroid metabolite that is the 11-deoxy derivative of CORTICOSTERONE and the 21-hydroxy derivative of PROGESTERONE 21-Hydroxyprogesterone,Cortexone,Deoxycorticosterone,Desoxycortone,11-Decorticosterone,21-Hydroxy-4-pregnene-3,20-dione,11 Decorticosterone,21 Hydroxy 4 pregnene 3,20 dione,21 Hydroxyprogesterone
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005355 Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Cirrhosis,Fibroses
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012965 Sodium Chloride A ubiquitous sodium salt that is commonly used to season food. Sodium Chloride, (22)Na,Sodium Chloride, (24)NaCl
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor

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