Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3
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 tetrasulfi...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-01-01
|
Series: | Redox Biology |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720310181 |
id |
doaj-9c4b002320374967bd1505c380a4ea8d |
---|---|
record_format |
Article |
spelling |
doaj-9c4b002320374967bd1505c380a4ea8d2020-12-31T04:42:00ZengElsevierRedox Biology2213-23172021-01-0138101813Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3Hai-Jian Sun0Si-Ping Xiong1Xu Cao2Lei Cao3Meng-Yuan Zhu4Zhi-Yuan Wu5Jin-Song Bian6Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, SingaporeDepartment of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu, 215000, China; Corresponding author. Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.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 κB (p65 NF-κB) 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-κB 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-κB and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1.http://www.sciencedirect.com/science/article/pii/S2213231720310181Diabetic nephropathyReactive oxygen speciesPolysulfidesHydrogen sulfideSIRT1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hai-Jian Sun Si-Ping Xiong Xu Cao Lei Cao Meng-Yuan Zhu Zhi-Yuan Wu Jin-Song Bian |
spellingShingle |
Hai-Jian Sun Si-Ping Xiong Xu Cao Lei Cao Meng-Yuan Zhu Zhi-Yuan Wu Jin-Song Bian Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3 Redox Biology Diabetic nephropathy Reactive oxygen species Polysulfides Hydrogen sulfide SIRT1 |
author_facet |
Hai-Jian Sun Si-Ping Xiong Xu Cao Lei Cao Meng-Yuan Zhu Zhi-Yuan Wu Jin-Song Bian |
author_sort |
Hai-Jian Sun |
title |
Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3 |
title_short |
Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3 |
title_full |
Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3 |
title_fullStr |
Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3 |
title_full_unstemmed |
Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3 |
title_sort |
polysulfide-mediated sulfhydration of sirt1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 nf-κb and stat3 |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2021-01-01 |
description |
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 κB (p65 NF-κB) 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-κB 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-κB and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1. |
topic |
Diabetic nephropathy Reactive oxygen species Polysulfides Hydrogen sulfide SIRT1 |
url |
http://www.sciencedirect.com/science/article/pii/S2213231720310181 |
work_keys_str_mv |
AT haijiansun polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 AT sipingxiong polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 AT xucao polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 AT leicao polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 AT mengyuanzhu polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 AT zhiyuanwu polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 AT jinsongbian polysulfidemediatedsulfhydrationofsirt1preventsdiabeticnephropathybysuppressingphosphorylationandacetylationofp65nfkbandstat3 |
_version_ |
1724365086953308160 |