Xu Hong, Zhang Li-Bo, Luo Yi-Yi, Wang Ling, Zhang Ye-Pin, Chen Pei-Qi, Ba Xue-Ying, Han Jian, Luo Heng
Department of Ophthalmology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China.
Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China.
World J Diabetes. 2024 May 15;15(5):958-976. doi: 10.4239/wjd.v15.i5.958.
Synaptotagmins (SYTs) are a family of 17 membrane transporters that function as calcium ion sensors during the release of Ca-dependent neurotransmitters and hormones. However, few studies have reported whether members of the SYT family play a role in glucose uptake in diabetic retinopathy (DR) through Ca/glucose transporter-1 (GLUT1) and the possible regulatory mechanism of SYTs.
To elucidate the role of the SYT family in the regulation of glucose transport in retinal pigment epithelial cells and explore its potential as a therapeutic target for the clinical management of DR.
DR was induced by streptozotocin in C57BL/6J mice and by high glucose medium in human retinal pigment epithelial cells (ARPE-19). Bioinformatics analysis, reverse transcriptase-polymerase chain reaction, Western blot, flow cytometry, ELISA, HE staining, and TUNEL staining were used for analysis.
Six differentially expressed proteins (SYT2, SYT3, SYT4, SYT7, SYT11, and SYT13) were found between the DR and control groups, and SYT4 was highly expressed. Hyperglycemia induces SYT4 overexpression, manipulates Ca influx to induce GLUT1 fusion with the plasma membrane, promotes abnormal expression of the glucose transporter GLUT1 and excessive glucose uptake, induces ARPE-19 cell apoptosis, and promotes DR progression. Parkin deficiency inhibits the proteasomal degradation of SYT4 in DR, resulting in SYT4 accumulation and enhanced GLUT1 fusion with the plasma membrane, and these effects were blocked by oe-Parkin treatment. Moreover, dysregulation of the myelin transcription factor 1 (Myt1)-induced transcription of SYT4 in DR further activated the SYT4-mediated stimulus-secretion coupling process, and this process was inhibited in the oe-MYT1-treated group.
Our study reveals the key role of SYT4 in regulating glucose transport in retinal pigment epithelial cells during the pathogenesis of DR and the underlying mechanism and suggests potential therapeutic targets for clinical DR.
突触结合蛋白（SYTs）是一个由17种膜转运蛋白组成的家族，在钙依赖性神经递质和激素释放过程中作为钙离子传感器发挥作用。然而，关于SYT家族成员是否通过钙/葡萄糖转运蛋白1（GLUT1）在糖尿病视网膜病变（DR）的葡萄糖摄取中发挥作用以及SYTs可能的调控机制，鲜有研究报道。
阐明SYT家族在视网膜色素上皮细胞葡萄糖转运调节中的作用，并探索其作为DR临床治疗靶点的潜力。
通过链脲佐菌素诱导C57BL/6J小鼠发生DR，并用高糖培养基处理人视网膜色素上皮细胞（ARPE-19）。采用生物信息学分析、逆转录-聚合酶链反应、蛋白质免疫印迹法、流式细胞术、酶联免疫吸附测定、苏木精-伊红染色和末端脱氧核苷酸转移酶介导的缺口末端标记染色进行分析。
在DR组和对照组之间发现了6种差异表达蛋白（SYT2、SYT3、SYT4、SYT7、SYT11和SYT13），其中SYT4高表达。高血糖诱导SYT4过表达，操纵钙内流以诱导GLUT1与质膜融合，促进葡萄糖转运蛋白GLUT1异常表达和葡萄糖过度摄取，诱导ARPE-19细胞凋亡，并促进DR进展。帕金森蛋白缺乏抑制DR中SYT4的蛋白酶体降解，导致SYT4积累并增强GLUT1与质膜的融合，而oe-Parkin处理可阻断这些效应。此外，DR中髓磷脂转录因子1（Myt1）诱导的SYT4转录失调进一步激活了SYT4介导的刺激-分泌偶联过程，而在oe-MYT1处理组中该过程受到抑制。
我们的研究揭示了SYT4在DR发病机制中调节视网膜色素上皮细胞葡萄糖转运的关键作用及其潜在机制，并提出了DR临床治疗的潜在靶点。
