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Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-?B and STAT3.

ABSTRACT: Diabetic kidney disease is known as a major cause of chronic kidney disease and end stage renal disease. Polysulfides, a class of chemical agents with a chain of sulfur atoms, are found to confer renal protective effects in acute kidney injury. However, whether a polysulfide donor, sodium tetrasulfide (Na₂S₄), confers protective effects against diabetic nephropathy remains unclear. Our results showed that Na₂S₄ treatment ameliorated renal dysfunctional and histological damage in diabetic kidneys through inhibiting the overproduction of inflammation cytokine and reactive oxygen species (ROS), as well as attenuating renal fibrosis and renal cell apoptosis. Additionally, the upregulated phosphorylation and acetylation levels of p65 nuclear factor ?B (p65 NF-?B) and signal transducer and activator of transcription 3 (STAT3) in diabetic nephropathy were abrogated by Na₂S₄ in a sirtuin-1 (SIRT1)-dependent manner. In renal tubular epithelial cells, Na₂S₄ directly sulfhydrated SIRT1 at two conserved CXXC domains (Cys371/374; Cys395/398), then induced dephosphorylation and deacetylation of its targeted proteins including p65 NF-?B and STAT3, thereby reducing high glucose (HG)-caused oxidative stress, cell apoptosis, inflammation response and epithelial-to-mesenchymal transition (EMT) progression. Most importantly, inactivation of SIRT1 by a specific inhibitor EX-527, small interfering RNA (siRNA), a de-sulfhydration reagent dithiothreitol (DTT), or mutation of Cys371/374 and Cys395/398 sites at SIRT1 abolished the protective effects of Na₂S₄ on diabetic kidney insulting. These results reveal that polysulfides may attenuate diabetic renal lesions via inactivation of p65 NF-?B and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1.

SUBMITTER: Sun HJ

PROVIDER: S-EPMC7718489 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3.

Sun Hai-Jian HJ Xiong Si-Ping SP Cao Xu X Cao Lei L Zhu Meng-Yuan MY Wu Zhi-Yuan ZY Bian Jin-Song JS

Redox biology 20201125

Diabetic kidney disease is known as a major cause of chronic kidney disease and end stage renal disease. Polysulfides, a class of chemical agents with a chain of sulfur atoms, are found to confer renal protective effects in acute kidney injury. However, whether a polysulfide donor, sodium tetrasulfide (Na2S4), confers protective effects against diabetic nephropathy remains unclear. Our results showed that Na2S4 treatment ameliorated renal dysfunctional ...[more]

PMID: 33279869

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Project description:Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by neurotropic polyomavirus, JC virus (JCV), a virus that causes lytic infection of CNS glial cells. After primary infection, JCV is controlled by the immune system but virus persists asymptomatically. Rarely, when immune function is impaired, it can reemerge to cause PML. The mechanisms of JCV persistence and reactivation are not well understood but our earlier work implicated epigenetic control by protein acetylation since histone deacetylase inhibitors such as trichostatin A (TSA) strongly stimulate JCV transcription. Since both TNF-α and TSA activate JCV transcription via the same unique NF-κB site in the JCV control region, we investigated a role for acetylation of NF-κB in JCV regulation. A site-directed mutagenesis strategy was employed targeting the known lysine acetylation sites of NF-κB p65: K218, K221, and K310. We individually mutated each lysine to arginine, which cannot be acetylated and retains a positive charge like lysine. K218R and K221R impaired transactivation of JCV early promoter transcription either alone or combined with TSA treatment or coexpression of acetyltransferase transcriptional coactivator p300 but K310R was largely without effect. Mutation of lysine to glutamine gives mutants with a negative charge like acetyllysine. However, K218Q and K221Q showed impaired activity and only K310Q showed enhanced transactivation. NF-κB acetylation can regulate several aspects of the process of activation including complex formation with IκB, translocation to the nucleus, and DNA binding and transcriptional activation. Cell fractionation studies revealed that the mutants had no defect in translocation to the nucleus whereas gel shift studies revealed reduced binding to the JCV NF-κB site. Thus, acetylation regulates NF-κB p65 activity toward JCV at the level of p65 binding to the JCV control region and activation of JCV transcription.

Dataset Information

Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-?B and STAT3.

Publications

Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3.

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