β-Arrestin-2 enhances endoplasmic reticulum stress-induced glomerular endothelial cell injury by activating transcription factor 6 in diabetic nephropathy.

IF 4.2 3区医学 Q1 ENDOCRINOLOGY & METABOLISM World Journal of Diabetes Pub Date : 2024-12-15 DOI:10.4239/wjd.v15.i12.2322

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

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Abstract

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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背景：目的：研究β-arrestin-2在DN条件下GENCs中的作用：方法：给8周大的C57BL/6J小鼠腹腔注射链脲佐菌素诱导DN。用含有 siRNA-β-arrestin-2、shRNA-激活转录因子 6（ATF6）、pCDNA-β-arrestin-2 或 pCDNA-ATF6 的质粒转染 GENCs。此外，还通过尾静脉注射含有 shRNA-β-arrestin-2 的腺相关病毒（AAV）给 DN 小鼠：结果：在 DN 患者和 DN 小鼠的 GENCs 中都观察到了β-arrestin-2 的上调。敲除β-arrestin-2可减少高糖处理的GENCs的细胞凋亡，而过表达ATF6可逆转这种情况。此外，过表达β-arrestin-2导致内质网（ER）应激的激活和GENCs的凋亡，而沉默ATF6可减轻这种应激。此外，通过注射 AAV-shRNA-β-arrestin-2 敲除β-arrestin-2 可减轻 DN 小鼠的肾损伤：结论：通过抑制 ATF6 介导的体内和体外 ER 应激，敲除 β-arrestin-2 可防止 GENC 细胞凋亡。因此，β-arrestin-2 可能是临床治疗 DN 患者的一个很有前景的治疗靶点。

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来源期刊

World Journal of Diabetes ENDOCRINOLOGY & METABOLISM-

自引率

2.40%

发文量

909

期刊介绍： The WJD is a high-quality, peer reviewed, open-access journal. The primary task of WJD is to rapidly publish high-quality original articles, reviews, editorials, and case reports in the field of diabetes. In order to promote productive academic communication, the peer review process for the WJD is transparent; to this end, all published manuscripts are accompanied by the anonymized reviewers’ comments as well as the authors’ responses. The primary aims of the WJD are to improve diagnostic, therapeutic and preventive modalities and the skills of clinicians and to guide clinical practice in diabetes. Scope: Diabetes Complications, Experimental Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Diabetes, Gestational, Diabetic Angiopathies, Diabetic Cardiomyopathies, Diabetic Coma, Diabetic Ketoacidosis, Diabetic Nephropathies, Diabetic Neuropathies, Donohue Syndrome, Fetal Macrosomia, and Prediabetic State.