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Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

AIMS: Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator o...

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Autores principales: Yang, Shikun, Zhao, Li, Han, Yachun, Liu, Yu, Chen, Chao, Zhan, Ming, Xiong, Xiaofen, Zhu, Xuejing, Xiao, Li, Hu, Chun, Liu, Fuyou, Zhou, Zhiguang, Kanwar, Yashpal S., Sun, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514499/
https://www.ncbi.nlm.nih.gov/pubmed/28728079
http://dx.doi.org/10.1016/j.redox.2017.07.002
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author Yang, Shikun
Zhao, Li
Han, Yachun
Liu, Yu
Chen, Chao
Zhan, Ming
Xiong, Xiaofen
Zhu, Xuejing
Xiao, Li
Hu, Chun
Liu, Fuyou
Zhou, Zhiguang
Kanwar, Yashpal S.
Sun, Lin
author_facet Yang, Shikun
Zhao, Li
Han, Yachun
Liu, Yu
Chen, Chao
Zhan, Ming
Xiong, Xiaofen
Zhu, Xuejing
Xiao, Li
Hu, Chun
Liu, Fuyou
Zhou, Zhiguang
Kanwar, Yashpal S.
Sun, Lin
author_sort Yang, Shikun
collection PubMed
description AIMS: Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression. RESULTS: We found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac-H3 expression in HK-2 cells under HG ambience. INNOVATION AND CONCLUSION: Our results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway.
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spelling pubmed-55144992017-07-27 Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc Yang, Shikun Zhao, Li Han, Yachun Liu, Yu Chen, Chao Zhan, Ming Xiong, Xiaofen Zhu, Xuejing Xiao, Li Hu, Chun Liu, Fuyou Zhou, Zhiguang Kanwar, Yashpal S. Sun, Lin Redox Biol Research Paper AIMS: Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression. RESULTS: We found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac-H3 expression in HK-2 cells under HG ambience. INNOVATION AND CONCLUSION: Our results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway. Elsevier 2017-07-04 /pmc/articles/PMC5514499/ /pubmed/28728079 http://dx.doi.org/10.1016/j.redox.2017.07.002 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Yang, Shikun
Zhao, Li
Han, Yachun
Liu, Yu
Chen, Chao
Zhan, Ming
Xiong, Xiaofen
Zhu, Xuejing
Xiao, Li
Hu, Chun
Liu, Fuyou
Zhou, Zhiguang
Kanwar, Yashpal S.
Sun, Lin
Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc
title Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc
title_full Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc
title_fullStr Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc
title_full_unstemmed Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc
title_short Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc
title_sort probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66shc
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514499/
https://www.ncbi.nlm.nih.gov/pubmed/28728079
http://dx.doi.org/10.1016/j.redox.2017.07.002
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