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Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage

Renal fibrosis is a common pathological outcome of various chronic kidney diseases, and as yet, there is no specific treatment. Dapagliflozin has shown renal protection in some clinical trials as a glucose-lowering drug, but its role and mechanism on renal fibrosis remain unclear. In this study, we...

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Autores principales: Zeng, Jianhua, Huang, Hao, Zhang, Yan, Lv, Xin, Cheng, Jiawei, Zou, Si Jue, Han, Yuanyuan, Wang, Songkai, Gong, Li, Peng, Zhangzhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028454/
https://www.ncbi.nlm.nih.gov/pubmed/36959860
http://dx.doi.org/10.3389/fphar.2023.1095487
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author Zeng, Jianhua
Huang, Hao
Zhang, Yan
Lv, Xin
Cheng, Jiawei
Zou, Si Jue
Han, Yuanyuan
Wang, Songkai
Gong, Li
Peng, Zhangzhe
author_facet Zeng, Jianhua
Huang, Hao
Zhang, Yan
Lv, Xin
Cheng, Jiawei
Zou, Si Jue
Han, Yuanyuan
Wang, Songkai
Gong, Li
Peng, Zhangzhe
author_sort Zeng, Jianhua
collection PubMed
description Renal fibrosis is a common pathological outcome of various chronic kidney diseases, and as yet, there is no specific treatment. Dapagliflozin has shown renal protection in some clinical trials as a glucose-lowering drug, but its role and mechanism on renal fibrosis remain unclear. In this study, we used a 0.2% adenine diet-induced renal fibrosis mouse model to investigate whether dapagliflozin could protect renal function and alleviate renal fibrosis in this animal model. In vivo, we found that dapagliflozin’s protective effect on renal fibrosis was associated with 1) sustaining mitochondrial integrity and respiratory chain complex expression, maintained the amount of mitochondria; 2) improving fatty acid oxidation level with increased expression of CPT1-α, PPAR-α, ACOX1, and ACOX2; 3) reducing inflammation and oxidative stress, likely via regulation of IL-1β, IL-6, TNF-α, MCP-1, cxcl-1 expression, and glutathione (GSH) activity, superoxide dismutase (SOD) and malondialdehyde (MDA) levels; and 4) inhibiting the activation of the TGF-β1/MAPK pathway. In HK2 cells treated with TGF-β1, dapagliflozin reduced the expression of FN and α-SMA, improved mitochondrial respiratory chain complex expression, and inhibited activation of the TGF-β1/MAPK pathway.
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spelling pubmed-100284542023-03-22 Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage Zeng, Jianhua Huang, Hao Zhang, Yan Lv, Xin Cheng, Jiawei Zou, Si Jue Han, Yuanyuan Wang, Songkai Gong, Li Peng, Zhangzhe Front Pharmacol Pharmacology Renal fibrosis is a common pathological outcome of various chronic kidney diseases, and as yet, there is no specific treatment. Dapagliflozin has shown renal protection in some clinical trials as a glucose-lowering drug, but its role and mechanism on renal fibrosis remain unclear. In this study, we used a 0.2% adenine diet-induced renal fibrosis mouse model to investigate whether dapagliflozin could protect renal function and alleviate renal fibrosis in this animal model. In vivo, we found that dapagliflozin’s protective effect on renal fibrosis was associated with 1) sustaining mitochondrial integrity and respiratory chain complex expression, maintained the amount of mitochondria; 2) improving fatty acid oxidation level with increased expression of CPT1-α, PPAR-α, ACOX1, and ACOX2; 3) reducing inflammation and oxidative stress, likely via regulation of IL-1β, IL-6, TNF-α, MCP-1, cxcl-1 expression, and glutathione (GSH) activity, superoxide dismutase (SOD) and malondialdehyde (MDA) levels; and 4) inhibiting the activation of the TGF-β1/MAPK pathway. In HK2 cells treated with TGF-β1, dapagliflozin reduced the expression of FN and α-SMA, improved mitochondrial respiratory chain complex expression, and inhibited activation of the TGF-β1/MAPK pathway. Frontiers Media S.A. 2023-03-07 /pmc/articles/PMC10028454/ /pubmed/36959860 http://dx.doi.org/10.3389/fphar.2023.1095487 Text en Copyright © 2023 Zeng, Huang, Zhang, Lv, Cheng, Zou, Han, Wang, Gong and Peng. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zeng, Jianhua
Huang, Hao
Zhang, Yan
Lv, Xin
Cheng, Jiawei
Zou, Si Jue
Han, Yuanyuan
Wang, Songkai
Gong, Li
Peng, Zhangzhe
Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
title Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
title_full Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
title_fullStr Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
title_full_unstemmed Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
title_short Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
title_sort dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting tgf-β1/mapk mediated mitochondrial damage
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028454/
https://www.ncbi.nlm.nih.gov/pubmed/36959860
http://dx.doi.org/10.3389/fphar.2023.1095487
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