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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
β-Arrestin-2 enhances endoplasmic reticulum stress-induced glomerular endothelial cell injury by activating transcription factor 6 in diabetic nephropathy
Jiang Liu, Xiao-Yun Song, Xiu-Ting Li, Mu Yang, Fang Wang, Ying Han, Ying Jiang, Yu-Xin Lei, Miao Jiang, Wen Zhang, Dong-Qi Tang
Jiang Liu, Wen Zhang, Dong-Qi Tang, Center for Gene and Immunotherapy, Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
Xiao-Yun Song, Mu Yang, Ying Jiang, Yu-Xin Lei, Center for Gene and Immunotherapy, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
Xiu-Ting Li, Medical Device and Pharmaceutical Packaging Inspection, Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection, Jinan 250101, Shandong Province, China
Fang Wang, Ying Han, Center of Animal, Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
Miao Jiang, Clinical Skill Training Centre, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
Co-corresponding authors: Wen Zhang and Dong-Qi Tang.
Author contributions: Liu J, Zhang W, and Tang DQ conceptualized and designed the research; Jiang Y and Jiang M screened the patients and acquired the clinical data; Wang F, Han Y, and Lei YX collected blood specimens and performed laboratory analysis; Liu J, Song XY, Li XT, and Yang M performed the experiments and data analysis; Liu J, Zhang W, and Tang DQ wrote the paper. All the authors have read and approved the final manuscript. Liu J proposed, designed, and performed the experiments and prepared the first draft of the manuscript. Both Zhang W and Tang DQ have played important and indispensable roles in the experimental design, data interpretation, and manuscript preparation as the co-corresponding authors. Zhang W and Tang DQ obtained the funds for this research project. Zhang W conceptualized, designed, and supervised the whole process of the project. Tang DQ was instrumental and responsible for data re-interpretation, figure plotting, comprehensive literature search, and preparation and submission of the current version of the manuscript with a new focus on ATF6 mediated endoplasmic reticulum stress of diabetic nephropathy and on potential underlying mechanisms. This collaboration between Zhang W and Tang DQ is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by Key Research and Development Program of Shandong Province, No. 2021CXGC011101; Special Fund for Taishan Scholars Project, No. tsqn202211324; National Natural Science Foundation of China, No. 81900669; Natural Science Foundation of Shandong Province, China, No. ZR2018PH007; and the Multidisciplinary Innovation Center for Nephrology of the Second Hospital of Shandong University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Research Ethics Committee of The Second Hospital of Shandong University, IACUC protocol number: KYLL-2020 (LW)-072.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Dong-Qi Tang, PhD, Academic Research, Center for Gene and Immunotherapy, Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Road, Jinan 250033, Shandong Province, China.
tangdq@sdu.edu.cn
Received: February 16, 2024
Revised: August 23, 2024
Accepted: September 18, 2024
Published online: December 15, 2024
Processing time: 275 Days and 23.4 Hours
BACKGROUND
Glomerular endothelial cell (GENC) injury is a characteristic of early-stage diabetic nephropathy (DN), and the investigation of potential therapeutic targets for preventing GENC injury is of clinical importance.
AIM
To investigate the role of β-arrestin-2 in GENCs under DN conditions.
METHODS
Eight-week-old C57BL/6J mice were intraperitoneally injected with streptozotocin to induce DN. GENCs were transfected with plasmids containing siRNA-β-arrestin-2, shRNA-activating transcription factor 6 (ATF6), pCDNA-β-arrestin-2, or pCDNA-ATF6. Additionally, adeno-associated virus (AAV) containing shRNA-β-arrestin-2 was administered via a tail vein injection in DN mice.
RESULTS
The upregulation of β-arrestin-2 was observed in patients with DN as well as in GENCs from DN mice. Knockdown of β-arrestin-2 reduced apoptosis in high glucose-treated GENCs, which was reversed by the overexpression of ATF6. Moreover, overexpression of β-arrestin-2 Led to the activation of endoplasmic reticulum (ER) stress and the apoptosis of GENCs which could be mitigated by silencing of ATF6. Furthermore, knockdown of β-arrestin-2 by the administration of AAV-shRNA-β-arrestin-2 alleviated renal injury in DN mice.
CONCLUSION
Knockdown of β-arrestin-2 prevents GENC apoptosis by inhibiting ATF6-mediated ER stress in vivo and in vitro. Consequently, β-arrestin-2 may represent a promising therapeutic target for the clinical management of patients with DN.
Core Tip: This study investigates the role of β-arrestin-2 in glomerular endothelial cells (GENCs) in the context of diabetic nephropathy (DN). Under DN conditions, upregulated β-arrestin-2 increases the expression of activating transcription factor 6 and facilitates its translocation into the nucleus. This activation of endoplasmic reticulum stress induces apoptosis of GENCs, exacerbating renal damage. Silencing β-arrestin-2 alleviates renal injury and GENC apoptosis both in vivo and in vitro, suggesting that β-arrestin-2 could be a promising therapeutic target for the clinical management of patients with DN.
