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J. Biol. Chem., Vol. 281, Issue 52, 40193-40200, December 29, 2006

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Smooth Muscle -Actin Deficiency in Myofibroblasts Leads to Enhanced Renal Tissue Fibrosis^*

Masanobu Takeji, Toshiki Moriyama^¶, Susumu Oseto, Noritaka Kawada, Masatsugu Hori, Enyu Imai, and Takeshi Miwa¹

From the Genome Information Research Center, Research Institute for Microbial Diseases, and Department of Nephrology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 and ^¶Health Care Center, Osaka University, Toyonaka, Osaka 560-0043, Japan

Myofibroblasts are a major source of proinflammatory cytokines and extracellular matrix in progressive tissue fibrosis leading to chronic organ failure. Myofibroblasts are characterized by de novo expression of smooth muscle -actin (SMA), which correlates with the extent of disease progression, although their exact role is unknown. In vitro cultured myofibroblasts from kidney of SMA knock-out mice demonstrate significantly more prominent cell motility, proliferation, and type-I procollagen expression than those of wild-type myofibroblasts. These pro-fibrotic properties are suppressed by adenovirus-mediated SMA re-expression, accompanied by down-regulation of focal adhesion proteins. In interstitial fibrosis model, tissue fibrosis area, proliferating interstitial cell number, and type-I procollagen expression are enhanced under SMA deficiency. In mesangioproliferative glomerulonephritis model, cell proliferation in the mesangial area is also enhanced in SMA knock-out mice. Adenoviral SMA introduction into renal interstitium obviously ameliorates tissue fibrosis in interstitial fibrosis model. These results indicate that SMA suppresses the pro-fibrotic properties of myofibroblasts, highlighting the significance of smooth muscle-related proteins in moderating chronic organ fibrosis under pathological conditions.

Received for publication, March 8, 2006 , and in revised form, November 2, 2006.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Genome Information Research Center, Research Inst. for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-8369; Fax: 81-6-6879-8372; E-mail: miwa{at}gen-info.osaka-u.ac.jp.

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