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SIRT1-dependent deacetylation of Txnip H3K9ac is critical for exenatide-improved diabetic kidney disease

Wang, Mei jun LU ; Cai, Xiang ; Liang, Ri ying ; Zhang, En ming LU ; Liang, Xiao qi ; Liang, Hua ; Fu, Chang ; Zhou, An dong ; Shi, Yi and Xu, Fen , et al. (2023) In Biomedicine and Pharmacotherapy 167.
Abstract

Glucagon-like peptide 1 receptor agonist exenatide (exendin-4) has potential protective capabilities against diabetic kidney disease (DKD). However, the underlying mechanism has not been fully elucidated. The expression of thioredoxin-interacting protein (Txnip) is upregulated during DKD progression by histone acetylation. Sirtuin 1 (SIRT1) is a deacetylase and is decreased in DKD, which indicates that it may regulate Txnip in this disease. Here, we used whole-body heterozygous Sirt1 knockout (Sirt1+/-) and kidney-specific Sirt1 knockout (KSK) mice to investigate whether SIRT1 regulates Txnip via histone deacetylation in DKD and exenatide-alleviated DKD. Exenatide substantially improved renal pathological damage, decreased... (More)

Glucagon-like peptide 1 receptor agonist exenatide (exendin-4) has potential protective capabilities against diabetic kidney disease (DKD). However, the underlying mechanism has not been fully elucidated. The expression of thioredoxin-interacting protein (Txnip) is upregulated during DKD progression by histone acetylation. Sirtuin 1 (SIRT1) is a deacetylase and is decreased in DKD, which indicates that it may regulate Txnip in this disease. Here, we used whole-body heterozygous Sirt1 knockout (Sirt1+/-) and kidney-specific Sirt1 knockout (KSK) mice to investigate whether SIRT1 regulates Txnip via histone deacetylation in DKD and exenatide-alleviated DKD. Exenatide substantially improved renal pathological damage, decreased the albumin-to-creatinine ratio (ACR), upregulated SIRT1 expression, and downregulated Txnip expression in kidneys of high-fat diet-treated C57BL/6J mice. However, these effects diminished in Sirt1+/- and KSK mice under exenatide treatment. The downregulation of Txnip expression by exendin-4 in high-glucose-treated SV40 MES13 cells was hampered during Sirt1 knockdown. These results demonstrate that kidney SIRT1 is indispensable in exenatide-improved DKD and downregulation of Txnip expression. Exendin-4 mechanistically downregulated Txnip histone 3 lysine 9 acetylation (H3K9ac) in a SIRT1-dependent manner and decreased spliced X-box binding protein 1 (XBP1s) recruitment to the Txnip promoter. These findings provide epigenetic evidence elucidating the specific mechanism for exenatide-mediated DKD alleviation and highlight the importance of Txnip as a promising therapeutic target for DKD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Diabetic kidney disease, Exenatide, Kidney-specific Sirt1 knockout, Txnip
in
Biomedicine and Pharmacotherapy
volume
167
article number
115515
publisher
Elsevier
external identifiers
  • pmid:37742607
  • scopus:85172939271
ISSN
0753-3322
DOI
10.1016/j.biopha.2023.115515
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2023 The Authors
id
5d6adf0c-16a7-401f-8a44-4c3c7dbc5391
date added to LUP
2023-12-04 16:20:36
date last changed
2024-04-17 12:36:25
@article{5d6adf0c-16a7-401f-8a44-4c3c7dbc5391,
  abstract     = {{<p>Glucagon-like peptide 1 receptor agonist exenatide (exendin-4) has potential protective capabilities against diabetic kidney disease (DKD). However, the underlying mechanism has not been fully elucidated. The expression of thioredoxin-interacting protein (Txnip) is upregulated during DKD progression by histone acetylation. Sirtuin 1 (SIRT1) is a deacetylase and is decreased in DKD, which indicates that it may regulate Txnip in this disease. Here, we used whole-body heterozygous Sirt1 knockout (Sirt1<sup>+/-</sup>) and kidney-specific Sirt1 knockout (KSK) mice to investigate whether SIRT1 regulates Txnip via histone deacetylation in DKD and exenatide-alleviated DKD. Exenatide substantially improved renal pathological damage, decreased the albumin-to-creatinine ratio (ACR), upregulated SIRT1 expression, and downregulated Txnip expression in kidneys of high-fat diet-treated C57BL/6J mice. However, these effects diminished in Sirt1<sup>+/-</sup> and KSK mice under exenatide treatment. The downregulation of Txnip expression by exendin-4 in high-glucose-treated SV40 MES13 cells was hampered during Sirt1 knockdown. These results demonstrate that kidney SIRT1 is indispensable in exenatide-improved DKD and downregulation of Txnip expression. Exendin-4 mechanistically downregulated Txnip histone 3 lysine 9 acetylation (H3K9ac) in a SIRT1-dependent manner and decreased spliced X-box binding protein 1 (XBP1s) recruitment to the Txnip promoter. These findings provide epigenetic evidence elucidating the specific mechanism for exenatide-mediated DKD alleviation and highlight the importance of Txnip as a promising therapeutic target for DKD.</p>}},
  author       = {{Wang, Mei jun and Cai, Xiang and Liang, Ri ying and Zhang, En ming and Liang, Xiao qi and Liang, Hua and Fu, Chang and Zhou, An dong and Shi, Yi and Xu, Fen and Cai, Meng yin}},
  issn         = {{0753-3322}},
  keywords     = {{Diabetic kidney disease; Exenatide; Kidney-specific Sirt1 knockout; Txnip}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Biomedicine and Pharmacotherapy}},
  title        = {{SIRT1-dependent deacetylation of Txnip H3K9ac is critical for exenatide-improved diabetic kidney disease}},
  url          = {{http://dx.doi.org/10.1016/j.biopha.2023.115515}},
  doi          = {{10.1016/j.biopha.2023.115515}},
  volume       = {{167}},
  year         = {{2023}},
}