1. Academic Validation
  2. Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation

Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation

  • Mol Med. 2023 Oct 27;29(1):147. doi: 10.1186/s10020-023-00735-1.
Jiayu Song 1 Hongri Wang 1 Jingyi Sheng 1 Wen Zhang 2 Juan Lei 1 Weihua Gan 3 Fangfang Cai 4 Yunwen Yang 5
Affiliations

Affiliations

  • 1 Department of Pediatric Nephrology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, Jiangsu, China.
  • 2 Department of Nephrology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 Department of Pediatric Nephrology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, Jiangsu, China. weihuagan@njmu.edu.cn.
  • 4 School of Biopharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. 1520210061@cpu.edu.cn.
  • 5 Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. yangyunwen@njmu.edu.cn.
Abstract

Background: Chronic kidney disease (CKD) involves a variety of pathological processes, and Ferroptosis plays a vital role in CKD progression. Targeting Ferroptosis is a promising strategy for the treatment of CKD. However, inhibitors of Ferroptosis have not been used in the clinical treatment of CKD. Vitexin is a natural flavonoid with many biological activities and protective effects against various diseases. However, whether vitexin can prevent the progression of CKD is not known.

Methods: In vivo, the effect of vitexin on CKD was evaluated by using mouse models of unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion (UIR). Western blotting, Sirius red staining and transmission electron microscopy were used to analyze renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. In vitro, CCK8 assays and lipid peroxidation assays were performed to analyze cell viability and lipid peroxidation in human renal tubular epithelial cells (HK2 cells) induced by erastin. The activation of renal fibroblasts (NRK-49 F cells) was also analyzed. Additionally, an in-silico protein-drug docking model and coimmunoprecipitation were performed to determine the direct substrate of vitexin.

Results: In vivo, vitexin treatment significantly ameliorated renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. Additionally, our results showed that vitexin significantly attenuated UUO- and UIR-induced Ferroptosis in renal tubular epithelial cells by upregulating Glutathione Peroxidase 4 (GPX4) protein levels and inhibiting lipid peroxidation in mouse kidneys. In vitro, treatment with vitexin inhibited erastin-induced Ferroptosis in HK2 cells. Moreover, vitexin inhibited the expression of collagen I and α-SMA (alpha-smooth muscle actin) in NRK-49 F cells induced by the supernatant of erastin-treated HK2 cells. Mechanistically, our results suggested that vitexin could activate the NRF2/heme oxygenase-1 (HO-1) pathway by inhibiting the KEAP1- and ubiquitination-mediated degradation of NRF2, thereby increasing the expression of GPX4, and further inhibiting lipid peroxidation and Ferroptosis. Additionally, knockout of NRF2 greatly inhibited the antiferroptotic effects of vitexin.

Conclusions: Taken together, our results indicate that vitexin can protect against renal tubular epithelial cell Ferroptosis in CKD by activating the KEAP1/NRF2/HO-1 pathway and is a promising drug to treat CKD.

Keywords

Antioxidant; CKD; Ferroptosis; NRF2; Vitexin.

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