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Published on: May 10, 2024
β-Arrestin-2 enhances endoplasmic reticulum stress-induced glomerular endothelial cell injury by activating
Jiang Liu1, Xiao-Yun Song2, Xiu-Ting Li3
1Center for Gene and Immunotherapy, Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China.
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.
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