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  3. Endoplasmic reticulum stress-triggered ferroptosis via the XBP1-Hrd1-Nrf2 pathway induces EMT progression in diabetic nephropathy

Endoplasmic reticulum stress-triggered ferroptosis via the XBP1-Hrd1-Nrf2 pathway induces EMT progression in diabetic nephropathy

  • Biomed Pharmacother. 2023 May 22;164:114897. doi: 10.1016/j.biopha.2023.114897.
Zijun Liu 1,  Ping Nan 2,  Yihui Gong 3,  Ling Tian 4,  Yin Zheng 5,  Zhongming Wu 6
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China. Electronic address: [email protected].
  • 2 Department of Obster & Gynecol, Shengli Oilfield Center Hospital, Dongying, Shandong 257000, China. Electronic address: [email protected].
  • 3 NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China. Electronic address: [email protected].
  • 4 NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China. Electronic address: [email protected].
  • 5 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China. Electronic address: [email protected].
  • 6 NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China. Electronic address: [email protected].
PMID: 37224754 DOI: 10.1016/j.biopha.2023.114897
Abstract

Diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis caused by epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Although Ferroptosis promotes DN development, the specific pathological process that is affected by Ferroptosis in DN remains unclear. Herein, EMT-related changes, including increased α-smooth muscle actin (α-SMA) and Vimentin expression and decreased E-cadherin expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose-cultured human renal proximal tubular (HK-2) cells. Treatment with ferrostatin-1 (Fer-1) ameliorated these changes and rescued renal pathological injury in diabetic mice. Interestingly, endoplasmic reticulum stress (ERS) was activated during EMT progression in DN. Inhibiting ERS improved the expression of EMT-associated indicators and further rescued the characteristic changes in Ferroptosis caused by high glucose, including Reactive Oxygen Species (ROS) accumulation, iron overload, increased lipid peroxidation product generation, and reduced mitochondrial cristae. Moreover, overexpression of XBP1 increased Hrd1 expression and inhibited NFE2-related factor 2 (Nrf2) expression, which could enhance cell susceptibility to Ferroptosis. Co-immunoprecipitation (Co-IP) and ubiquitylation assays indicated that Hrd1 interacted with and ubiquitinated Nrf2 under high-glucose conditions. Collectively, our results demonstrated that ERS triggers ferroptosis-related EMT progression through the XBP1-Hrd1-Nrf2 pathway, which provides new insights into potential mechanisms for delaying EMT progression in DN.

Keywords

Diabetic nephropathy; Endoplasmic reticulum stress; Epithelial-mesenchymal transition; Ferroptosis; XBP1-Hrd1-Nrf2 pathway.

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