Role of Transcription Factor Acetylation in Diabetic Kidney Disease

  1. John Cijiang He1,7
  1. 1Departments of Medicine and Nephrology, Mount Sinai School of Medicine, New York, NY
  2. 2Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
  3. 3Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P.R. China
  4. 4Department of Endocrinology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, P.R. China
  5. 5Division of Nephrology, Jacobi Medical Center, Bronx, NY
  6. 6Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY
  7. 7Renal Section, James J. Peters VA Medical Center, Bronx, NY
  1. Corresponding author: John C. He, cijiang.he{at}


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; STAT3 abrogated AGE-induced expression of NF-kB 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 bromo and extra terminal (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.

  • Received November 27, 2013.
  • Accepted February 10, 2014.

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