1. Academic Validation
  2. Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation

Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation

  • World J Diabetes. 2024 May 15;15(5):958-976. doi: 10.4239/wjd.v15.i5.958.
Hong Xu 1 Li-Bo Zhang 1 Yi-Yi Luo 2 Ling Wang 3 Ye-Pin Zhang 4 Pei-Qi Chen 3 Xue-Ying Ba 2 Jian Han 2 Heng Luo 1 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Endocrinology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China.
  • 4 Department of Pathology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China.
  • 5 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. lh18987837533@163.com.
Abstract

Background: Synaptotagmins (SYTs) are a family of 17 membrane transporters that function as calcium ion sensors during the release of CA2+-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 CA2+/glucose transporter-1 (GLUT1) and the possible regulatory mechanism of SYTs.

Aim: 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.

Methods: 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.

Results: 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 CA2+ 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.

Conclusion: 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.

Keywords

Diabetic retinopathy; Glucose transporter-1; Myelin transcription factor 1; Parkin; Synaptotagmin 4.

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