title: Role of transcription factor acetylation in diabetic kidney disease.
abstract: Nuclear factor (NF)-κB and signal transducer and activator of transcription 3 (STAT3) play a critical role in diabetic nephropathy (DN). Sirtuin-1 (SIRT1) regulates transcriptional activation of target genes through protein deacetylation. Here, we determined the roles of Sirt1 and the effect of NF-κB (p65) and STAT3 acetylation in DN. We found that acetylation of p65 and STAT3 was increased in both mouse and human diabetic kidneys. In human podocytes, advanced glycation end products (AGEs) induced p65 and STAT3 acetylation and overexpression of acetylation-incompetent mutants of p65 and STAT3 abrogated AGE-induced expression of NF-κB and STAT3 target genes. Inhibition of AGE formation in db/db mice by pyridoxamine treatment attenuated proteinuria and podocyte injury, restored SIRT1 expression, and reduced p65 and STAT3 acetylation. Diabetic db/db mice with conditional deletion of SIRT1 in podocytes developed more proteinuria, kidney injury, and acetylation of p65 and STAT3 compared with db/db mice without SIRT1 deletion. Treatment of db/db mice with a bromodomain and extraterminal (BET)-specific bromodomain inhibitor (MS417) which blocks acetylation-mediated association of p65 and STAT3 with BET proteins, attenuated proteinuria, and kidney injury. Our findings strongly support a critical role for p65 and STAT3 acetylation in DN. Targeting protein acetylation could be a potential new therapy for DN.
authors.affiliation: Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, NY.
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Haibing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Jacobi Medical Center, Bronx, NY.
authors.forename: Belinda
authors.initials: B
authors.lastname: Jim
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, NY.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.affiliation: Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, NYRenal Section, James J. Peters VA Medical Center, Bronx, NY cijiang.he@mssm.edu.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051996:Transcription Factor RelA; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1