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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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1095487/full |
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| author | Jianhua Zeng Jianhua Zeng Jianhua Zeng Hao Huang Hao Huang Hao Huang Hao Huang Yan Zhang Yan Zhang Yan Zhang Xin Lv Xin Lv Xin Lv Jiawei Cheng Jiawei Cheng Jiawei Cheng Si Jue Zou Si Jue Zou Si Jue Zou Yuanyuan Han Yuanyuan Han Yuanyuan Han Songkai Wang Songkai Wang Songkai Wang Li Gong Li Gong Li Gong Zhangzhe Peng Zhangzhe Peng Zhangzhe Peng |
| author_facet | Jianhua Zeng Jianhua Zeng Jianhua Zeng Hao Huang Hao Huang Hao Huang Hao Huang Yan Zhang Yan Zhang Yan Zhang Xin Lv Xin Lv Xin Lv Jiawei Cheng Jiawei Cheng Jiawei Cheng Si Jue Zou Si Jue Zou Si Jue Zou Yuanyuan Han Yuanyuan Han Yuanyuan Han Songkai Wang Songkai Wang Songkai Wang Li Gong Li Gong Li Gong Zhangzhe Peng Zhangzhe Peng Zhangzhe Peng |
| author_sort | Jianhua Zeng |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T05:30:56Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T05:30:56Z |
| publishDate | 2023-03-01 |
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| spelling | doaj.art-17a9f759e1f94615816a3ce38778f30e2023-03-07T08:31:37ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.10954871095487Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damageJianhua Zeng0Jianhua Zeng1Jianhua Zeng2Hao Huang3Hao Huang4Hao Huang5Hao Huang6Yan Zhang7Yan Zhang8Yan Zhang9Xin Lv10Xin Lv11Xin Lv12Jiawei Cheng13Jiawei Cheng14Jiawei Cheng15Si Jue Zou16Si Jue Zou17Si Jue Zou18Yuanyuan Han19Yuanyuan Han20Yuanyuan Han21Songkai Wang22Songkai Wang23Songkai Wang24Li Gong25Li Gong26Li Gong27Zhangzhe Peng28Zhangzhe Peng29Zhangzhe Peng30Department of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Cell Biology, School of Life Sciences, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaRenal 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.https://www.frontiersin.org/articles/10.3389/fphar.2023.1095487/fullrenal fibrosisdapagliflozinmitochondrial damageTGF-β1/MAPK pathwayoxidative stress |
| spellingShingle | Jianhua Zeng Jianhua Zeng Jianhua Zeng Hao Huang Hao Huang Hao Huang Hao Huang Yan Zhang Yan Zhang Yan Zhang Xin Lv Xin Lv Xin Lv Jiawei Cheng Jiawei Cheng Jiawei Cheng Si Jue Zou Si Jue Zou Si Jue Zou Yuanyuan Han Yuanyuan Han Yuanyuan Han Songkai Wang Songkai Wang Songkai Wang Li Gong Li Gong Li Gong Zhangzhe Peng Zhangzhe Peng Zhangzhe Peng Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage Frontiers in Pharmacology renal fibrosis dapagliflozin mitochondrial damage TGF-β1/MAPK pathway oxidative stress |
| 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 | renal fibrosis dapagliflozin mitochondrial damage TGF-β1/MAPK pathway oxidative stress |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1095487/full |
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