1. Academic Validation
  2. Empagliflozin attenuates the renal tubular ferroptosis in diabetic kidney disease through AMPK/NRF2 pathway

Empagliflozin attenuates the renal tubular ferroptosis in diabetic kidney disease through AMPK/NRF2 pathway

  • Free Radic Biol Med. 2023 Feb 1;195:89-102. doi: 10.1016/j.freeradbiomed.2022.12.088.
QianYu Lu 1 LiJiao Yang 1 Jing-Jie Xiao 2 Qing Liu 2 LiHua Ni 1 Jun-Wei Hu 1 Hong Yu 2 XiaoYan Wu 3 Bai-Fang Zhang 4
Affiliations

Affiliations

  • 1 Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 2 Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
  • 3 Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: wuxiaoyan2k6@whu.edu.cn.
  • 4 Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China. Electronic address: zbfwq@whu.edu.cn.
Abstract

Renal tubular damage plays a key role in the pathogenesis of diabetic kidney disease (DKD), and one of the main pathological process associated with DKD in diabetic mice is the Ferroptosis, a novel form of cell death caused by iron-dependent lipid peroxidation. Several researches suggested that empagliflozin may treat renal injury, but its effects on diabetic-related Ferroptosis and underlying mechanisms were not fully elucidated. In this study, the influence of empagliflozin on renal injury was evaluated in vivo and in vitro in a mouse model and in high-glucose (HG) or Erastin-stimulated renal HK-2 cell line, respectively. Ferroptosis-related markers were assessed, including GSH, labile iron levels, and Ferroptosis regulators by Western blot, qRT-PCR, immunohistochemistry, and immunofluorescence. The level of malondialdehyde (MDA) and the fluorescence intensity of BODIPY probe indicated the level of lipid peroxidation. It was demonstrated that solute carrier family 7, member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) were less expressed in renal biopsy samples from patients affected by DKD than in those from non-diabetic renal disease patients (NDRD), proving the Ferroptosis of tubular epithelial cells in case of DKD. Furthermore, empagliflozin markedly decreased the Ferroptosis impairment in DKD mice, as well as in HG model of HK-2 cells. Our investigations showed the ability of empagliflozin to suppress Ferroptosis was partially countered by AMP-activated protein kinase (AMPK) inhibitor, which led to a reduction of the nuclear translocation of the antioxidant transcription factor NFE2-related factor 2 (NRF2) and downregulation of target genes such as GPX4, ferritin heavy chain 1 (FTH1), and SLC7A11, while AMPK agonists were responsible for the enhancement of the protective effects of empagliflozin. Taken together, our findings showed that empagliflozin may prevent the development of Ferroptosis by promoting the AMPK-mediated NRF2 activation pathway, providing important insights for possible novel treatment approaches for DKD.

Keywords

AMP-activated protein kinase; Diabetic kidney disease; Empagliflozin; Ferroptosis; NFE2-related factor 2.

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