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J. Biol. Chem., Vol. 282, Issue 1, 151-158, January 5, 2007

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SIRT1 Inhibits Transforming Growth Factor -Induced Apoptosis in Glomerular Mesangial Cells via Smad7 Deacetylation^*

Shinji Kume, Masakazu Haneda, Keizo Kanasaki, Toshiro Sugimoto, Shin-ichi Araki, Keiji Isshiki, Motohide Isono, Takashi Uzu, Leonard Guarente^¶, Atsunori Kashiwagi, and Daisuke Koya^||1

From the Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan, The Second Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido 078-8510, Japan, ^¶Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and ^||Division of Endocrinology and Metabolism, Kanazawa Medical University, Kahoku-Gun, Ishikawa 920-0293, Japan

SIRT1, a class III histone deacetylase, is considered a key regulator of cell survival and apoptosis through its interaction with nuclear proteins. In this study, we have examined the likelihood and role of the interaction between SIRT1 and Smad7, which mediates transforming growth factor (TGF)-induced apoptosis in renal glomerular mesangial cells. Immunoprecipitation analysis revealed that SIRT1 directly interacts with the N terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (Lys-64 and -70) on Smad7. In mesangial cells, the Smad7 expression level was reduced by SIRT1 overexpression and increased by SIRT1 knockdown. SIRT1-mediated deacetylation of Smad7 enhanced Smad ubiquitination regulatory factor 1 (Smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of Smad7 in SIRT1-overexpressing mesangial cells. Stimulation by TGF or overexpression of Smad7 induced mesangial cell apoptosis, as assessed by morphological apoptotic changes (nuclear condensation) and biological apoptotic markers (cleavages of caspase3 and poly(ADP-ribose) polymerase). However, TGF failed to induce apoptosis in Smad7 knockdown mesangial cells, indicating that Smad7 mainly mediates TGF-induced apoptosis of mesangial cells. Finally, SIRT1 overexpression attenuated both Smad7- and TGF-induced mesangial cell apoptosis, whereas SIRT1 knockdown enhanced this apoptosis. We have concluded that Smad7 is a new target molecule for SIRT1 and SIRT1 attenuates TGF-induced mesangial cell apoptosis through acceleration of Smad7 degradation. Our results suggest that up-regulation of SIRT1 deacetylase activity is a potentially useful therapeutic strategy for prevention of TGF-related kidney disease through its effect on cell survival.

Received for publication, June 20, 2006 , and in revised form, November 1, 2006.

^* This study was supported by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to D. K.). 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: Division of Endocrinology and Metabolism, Kanazawa Medical University, Kahoku-Gun, Ishikawa 920-0293, Japan. Tel.: 81-76-286-2211; Fax: 81-76-286-6927; E-mail address: koya0516{at}kanazawa-med.ac.jp.

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