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

Jianhua Zeng; Hao Huang; Yan Zhang; Xin Lv; Jiawei Cheng; Si Jue Zou; Yuanyuan Han; Songkai Wang; Li Gong; Zhangzhe Peng

doi:10.3389/fphar.2023.1095487

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

Front Pharmacol. 2023 Mar 7:14:1095487. doi: 10.3389/fphar.2023.1095487. eCollection 2023.

Authors

Jianhua Zeng^{1

2

3}, Hao Huang^{1

2

3

4}, Yan Zhang^{1

2

3}, Xin Lv^{1

2

3}, Jiawei Cheng^{1

2

3}, Si Jue Zou^{1

2

3}, Yuanyuan Han^{1

2

3}, Songkai Wang^{1

2

3}, Li Gong^{1

2

3}, Zhangzhe Peng^{1

2

3}

Affiliations

¹ Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
² Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China.

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: TGF-β1/MAPK pathway; dapagliflozin; mitochondrial damage; oxidative stress; renal fibrosis.

Grants and funding

This project was supported by Major Program of National Natural Science Foundation of China (82090024); General Programs of National Natural Science Foundation of China (82173877); the Key Research and Development Program of Hunan Province (2021SK 2015); Outstanding Youth Foundation of Natural Science Foundation of Hunan Province (2022JJ10100); China Postdoctoral Science Foundation (2020TQ0363 and 2020M682598); the Natural Science Foundation of Hunan Province (2021JJ40992); and the Youth Science Foundation of Xiangya Hospital (2021Q11); the Fundamental Research Funds for the Central Universities of Central South University (2022ZZTS0941).