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CCAAT/Enhancer-Binding Protein Contributes to Myofibroblast Transdifferentiation and Renal Disease Progression

Masanobu Takeji^*,, Noritaka Kawada^*,, Toshiki Moriyama^*,, Katsuyuki Nagatoya^*, Susumu Oseto^*, Shizuo Akira, Masatsugu Hori^*, Enyu Imai^* and Takeshi Miwa

*Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Genome Information Research Center, Osaka University, Suita, Osaka, Japan; School of Health and Sport Sciences, Osaka University, Toyonaka, Osaka, Japan; and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

Correspondence to Dr. Toshiki Moriyama, Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. Phone: +81-6-6879-3632; Fax: +81-6-6879-3639; E-mail: moriyama{at}medone.med.osaka-u.ac.jp

ABSTRACT. Myofibroblasts are pivotal participants in pathologic processes in a wide variety of organs, such as lung, liver, and kidney, by producing several inflammatory cytokines and extracellular matrices. The mechanism by which transdifferentiation from original cell to myofibroblast occurs, however, is still unclear. The expression of smooth muscle -actin (SMA) is the most characteristic feature of myofibroblasts; therefore, it was speculated that any factors that promote SMA expression might be the key to transdifferentiation to myofibroblasts and disease exacerbation. A transcription factor CCAAT/enhancer-binding protein (C/EBP) was identified and demonstrated to bind to sequences including the CArG motif from SMA intron 1 and to increase transcriptional activity of this promoter. Expression of SMA and C/EBP in the glomerular area was upregulated in rat anti-Thy1 glomerulonephritis and mouse Habu-venom glomerulonephritis, both of which are models of mesangioproliferative glomerulonephritis. In the latter model, C/EBP knockout mice demonstrated significantly less SMA expression in the glomerular area on day 8 and less renal functional deterioration on day 14, compared with wild-type mice. These data suggest an important role for C/EBP in myofibroblast transdifferentiation and glomerulonephritis exacerbation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673