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Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum
BACKGROUND: Acute kidney injury (AKI) is one of the major risk factors for progression to chronic kidney disease (CKD) and renal fibrosis. However, effective therapies remain poorly understood. Here, we examined the renoprotective effects of melatonin and poricoic acid A (PAA) isolated from the surf...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696851/ https://www.ncbi.nlm.nih.gov/pubmed/31452866 http://dx.doi.org/10.1177/2040622319869116 |
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author | Chen, Dan-Qian Cao, Gang Zhao, Hui Chen, Lin Yang, Tian Wang, Ming Vaziri, Nosratola D. Guo, Yan Zhao, Ying-Yong |
author_facet | Chen, Dan-Qian Cao, Gang Zhao, Hui Chen, Lin Yang, Tian Wang, Ming Vaziri, Nosratola D. Guo, Yan Zhao, Ying-Yong |
author_sort | Chen, Dan-Qian |
collection | PubMed |
description | BACKGROUND: Acute kidney injury (AKI) is one of the major risk factors for progression to chronic kidney disease (CKD) and renal fibrosis. However, effective therapies remain poorly understood. Here, we examined the renoprotective effects of melatonin and poricoic acid A (PAA) isolated from the surface layer of Poria cocos, and investigated the effects of combined therapy on the interaction of TGF-β/Smad and Wnt/β-catenin in a rat model of renal ischemia-reperfusion injury (IRI) and hypoxia/reoxygenation (H/R) or TGF-β1-induced HK-2 cells. METHODS: Western blot and immunohistochemical staining were used to examine protein expression, while qRT-PCR was used to examine mRNA expression. Coimmunoprecipitation, chromatin immunoprecipitation, RNA interference, and luciferase reporter gene analysis were employed to explore the mechanisms of PAA and melatonin’s renoprotective effects. RESULTS: PAA and combined therapy exhibited renoprotective and antifibrotic effects, but the underlying mechanisms were different during AKI-to-CKD continuum. Melatonin suppressed Smad-dependent and Smad-independent pathways, while PAA selectively inhibited Smad3 phosphorylation through distrupting the interactions of Smad3 with TGFβRI and SARA. Further studies demonstrated that the inhibitory effects of melatonin and PAA were partially depended on Smad3, especially PAA. Melatonin and PAA also inhibited the Wnt/β-catenin pathway and its profibrotic downstream targets, and PAA performed better. We further determined that IRI induced a nuclear Smad3/β-catenin complex, while melatonin and PAA disturbed the interaction of Smad3 and β-catenin, and supplementing with PAA could enhance the inhibitory effects of melatonin on the TGF-β/Smad and Wnt/β-catenin pathways. CONCLUSIONS: Combined melatonin and PAA provides a promising therapeutic strategy to treat renal fibrosis during the AKI-to-CKD continuum. |
format | Online Article Text |
id | pubmed-6696851 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-66968512019-08-26 Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum Chen, Dan-Qian Cao, Gang Zhao, Hui Chen, Lin Yang, Tian Wang, Ming Vaziri, Nosratola D. Guo, Yan Zhao, Ying-Yong Ther Adv Chronic Dis Original Research BACKGROUND: Acute kidney injury (AKI) is one of the major risk factors for progression to chronic kidney disease (CKD) and renal fibrosis. However, effective therapies remain poorly understood. Here, we examined the renoprotective effects of melatonin and poricoic acid A (PAA) isolated from the surface layer of Poria cocos, and investigated the effects of combined therapy on the interaction of TGF-β/Smad and Wnt/β-catenin in a rat model of renal ischemia-reperfusion injury (IRI) and hypoxia/reoxygenation (H/R) or TGF-β1-induced HK-2 cells. METHODS: Western blot and immunohistochemical staining were used to examine protein expression, while qRT-PCR was used to examine mRNA expression. Coimmunoprecipitation, chromatin immunoprecipitation, RNA interference, and luciferase reporter gene analysis were employed to explore the mechanisms of PAA and melatonin’s renoprotective effects. RESULTS: PAA and combined therapy exhibited renoprotective and antifibrotic effects, but the underlying mechanisms were different during AKI-to-CKD continuum. Melatonin suppressed Smad-dependent and Smad-independent pathways, while PAA selectively inhibited Smad3 phosphorylation through distrupting the interactions of Smad3 with TGFβRI and SARA. Further studies demonstrated that the inhibitory effects of melatonin and PAA were partially depended on Smad3, especially PAA. Melatonin and PAA also inhibited the Wnt/β-catenin pathway and its profibrotic downstream targets, and PAA performed better. We further determined that IRI induced a nuclear Smad3/β-catenin complex, while melatonin and PAA disturbed the interaction of Smad3 and β-catenin, and supplementing with PAA could enhance the inhibitory effects of melatonin on the TGF-β/Smad and Wnt/β-catenin pathways. CONCLUSIONS: Combined melatonin and PAA provides a promising therapeutic strategy to treat renal fibrosis during the AKI-to-CKD continuum. SAGE Publications 2019-08-14 /pmc/articles/PMC6696851/ /pubmed/31452866 http://dx.doi.org/10.1177/2040622319869116 Text en © The Author(s), 2019 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Research Chen, Dan-Qian Cao, Gang Zhao, Hui Chen, Lin Yang, Tian Wang, Ming Vaziri, Nosratola D. Guo, Yan Zhao, Ying-Yong Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum |
title | Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum |
title_full | Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum |
title_fullStr | Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum |
title_full_unstemmed | Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum |
title_short | Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum |
title_sort | combined melatonin and poricoic acid a inhibits renal fibrosis through modulating the interaction of smad3 and β-catenin pathway in aki-to-ckd continuum |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696851/ https://www.ncbi.nlm.nih.gov/pubmed/31452866 http://dx.doi.org/10.1177/2040622319869116 |
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