SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells

Yang, Shu1,2,3; Yang, Guangyan1,2; Wang, Xinyu1,2; Xiang, Jiaqing1,2; Kang, Lin1,2,3,4; Liang, Zhen1,2,3

2023-09-30

10.1038/s41419-023-06169-1

CELL DEATH & DISEASE   Impact Factor & Quartile

2041-4889

Transforming growth factor-beta (TGF-beta) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-beta-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-beta signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-beta, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.

SCI

English

Corresponding

This work was supported by grants from the National Natural Science Foundation of China (82370876 to S.Y., 82170842 and 82371572 to Z.L., 82171556 to L.K.), Shenzhen Sustainable Development Science and Technology Special Project, China (No. KCXFZ2020122117["82370876","82170842","82371572","82171556"] ; National Natural Science Foundation of China[KCXFZ20201221173600001] ; Shenzhen Sustainable Development Science and Technology Special Project, China[JCYJ20220818102605013]

Cell Biology

Cell Biology

WOS:001076663800001

SPRINGERNATURE

Web of Science

1.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Dept Geriatr, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
3.Jinan Univ, Shenzhen Peoples Hosp, The Clin Med Coll 2, Guangdong Prov Clin Res Ctr Geriatr,Shenzhen Clin, Shenzhen 518020, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Biobank Natl Innovat Ctr Adv Med Devices, Shenzhen, Peoples R China

Yang, Shu,Yang, Guangyan,Wang, Xinyu,et al. SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells[J]. CELL DEATH & DISEASE,2023,14(9).

Yang, Shu,Yang, Guangyan,Wang, Xinyu,Xiang, Jiaqing,Kang, Lin,&Liang, Zhen.(2023).SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells.CELL DEATH & DISEASE,14(9).

Yang, Shu,et al."SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells".CELL DEATH & DISEASE 14.9(2023).