2. Academic Validation
  3. Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy

Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy

  • Biochem Biophys Res Commun. 2024 Aug 20:721:149972. doi: 10.1016/j.bbrc.2024.149972.
Xiaojiao Zeng 1,  Yuanyuan Zhang 1,  Ling Tian 1,  Yin Zheng 2,  Jingyun Zhang 3,  Zhongming Wu 4
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.
  • 2 Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021 China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong, 250012, China.
  • 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; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021 China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
PMID: 38772213 DOI: 10.1016/j.bbrc.2024.149972
Abstract

Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in Reactive Oxygen Species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.

Keywords

Diabetic nephropathy; Endoplasmic reticulum stress; NFE2-Related factor 2; Reactive oxygen species.

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