1. Academic Validation
  2. TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy

TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy

  • Cell Death Dis. 2023 Sep 1;14(9):583. doi: 10.1038/s41419-023-06111-5.
Yan Li # 1 Lingpeng Zhu # 1 2 Meng-Xia Cai 1 Zi-Li Wang 1 Miao Zhuang 1 Cheng-Ye Tan 1 Tian-Hua Xie 1 Yong Yao 3 Ting-Ting Wei 4 5
Affiliations

Affiliations

  • 1 Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China.
  • 2 Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China.
  • 3 Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China. yongyao@njmu.edu.cn.
  • 4 Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China. tingtingwei@njmu.edu.cn.
  • 5 Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China. tingtingwei@njmu.edu.cn.
  • # Contributed equally.
Abstract

Diabetic retinopathy (DR) is a serious and relatively under-recognized complication of diabetes. Müller glial cells extend throughout the retina and play vital roles in maintaining retinal homeostasis. Previous studies have demonstrated that TGR5, a member of the bile acid-activated GPCR family, could ameliorate DR. However, the role of TGR5 in regulating Müller cell function and the underlying mechanism remains to be ascertained. To address this, high glucose (HG)-treated human Müller cells and streptozotocin-treated Sprague-Dawley rats were used in the study. The IP3R1-GRP75-VDAC1 axis and mitochondrial function were assessed after TGR5 ablation or agonism. Cytosolic mitochondrial DNA (mtDNA)-mediated cGAS-STING activation was performed. The key markers of retinal vascular leakage, Apoptosis, and inflammation were examined. We found that mitochondrial CA2+ overload and mitochondrial dysfunction were alleviated by TGR5 agonist. Mechanically, TGR5 blocked the IP3R1-GRP75-VDAC1 axis mediated CA2+ efflux from the endoplasmic reticulum into mitochondria under diabetic condition. Mitochondrial CA2+ overload led to the opening of the mitochondrial permeability transition pore and the release of mitochondrial DNA (mtDNA) into the cytosol. Cytoplasmic mtDNA bound to cGAS and upregulated 2'3' cyclic GMP-AMP. Consequently, STING-mediated inflammatory responses were activated. TGR5 agonist prevented retinal injury, whereas knockdown of TGR5 exacerbated retinal damage in DR rats, which was rescued by the STING Inhibitor. Based on the above results, we propose that TGR5 might be a novel therapeutic target for the treatment of DR.

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