Frontiers in Pharmacology (Mar 2023)
Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
- 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
Affiliations
- Jianhua Zeng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Jianhua Zeng
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Jianhua Zeng
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Hao Huang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Hao Huang
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Hao Huang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Hao Huang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China
- Yan Zhang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Yan Zhang
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Yan Zhang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Xin Lv
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Xin Lv
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Xin Lv
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Jiawei Cheng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Jiawei Cheng
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Jiawei Cheng
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Si Jue Zou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Si Jue Zou
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Si Jue Zou
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Yuanyuan Han
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Yuanyuan Han
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Yuanyuan Han
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Songkai Wang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Songkai Wang
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Songkai Wang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Li Gong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Li Gong
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Li Gong
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Zhangzhe Peng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Zhangzhe Peng
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China
- Zhangzhe Peng
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- DOI
- https://doi.org/10.3389/fphar.2023.1095487
- Journal volume & issue
-
Vol. 14
Abstract
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.
Keywords
