Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
Acta Biochim Biophys Sin (Shanghai). 2021 May 21;53(6):784-795. doi: 10.1093/abbs/gmab049.
Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces β-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced β-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.
自身抗体针对血管紧张素 II 型 1 型受体（AT1-AA）已在糖尿病患者的血清中发现。然而，目前尚不清楚 AT1-AA 是否诱导β细胞凋亡并参与糖尿病的发生发展。在这项研究中，通过主动免疫建立了 AT1-AA 阳性大鼠模型，并纯化了 AT1-AA IgG。用 AT1-AA 处理 INS-1 细胞，通过细胞计数试剂盒-8 测定、流式细胞术和 Western blot 分析分别检测细胞活力、细胞凋亡和自噬相关蛋白。结果表明，AT1-AA 的存在损害了胰岛功能，并增加了大鼠胰岛细胞的凋亡，并且随着免疫时间的延长，大鼠胰岛组织中的自噬水平逐渐升高。AT1-AA 显著降低 INS-1 细胞活力，促进细胞凋亡，并减少体外胰岛素分泌。此外，随着 AT1-AA 处理时间的延长，自噬水平逐渐增加。同时，确定自噬抑制剂 3-甲基腺嘌呤和血管紧张素 II 型 1 型受体（AT1R）阻滞剂替米沙坦的治疗可以改善体外和体内的胰岛素分泌和细胞凋亡。综上所述，推测自噬的上调导致 AT1-AA 诱导的β细胞凋亡和胰岛功能障碍，AT1R 介导了信号转导。
