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  3. Pericyte loss via glutaredoxin2 downregulation aggravates diabetes-induced microvascular dysfunction

Pericyte loss via glutaredoxin2 downregulation aggravates diabetes-induced microvascular dysfunction

  • Exp Eye Res. 2024 Aug 6:247:110025. doi: 10.1016/j.exer.2024.110025.
Chenshuang Li 1,  Xi Chen 2,  Siqi Zhang 3,  Chen Liang 4,  Qi Deng 5,  Xinnan Li 6,  Hong Yan 7
Affiliations

Affiliations

  • 1 Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, Shaanxi Province, China; Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China. Electronic address: lichenshuang0926@163.com.
  • 2 Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, Shaanxi Province, China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi Province, China. Electronic address: chenxi@med.nwu.edu.cn.
  • 3 Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, Shaanxi Province, China; Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China. Electronic address: siqistdio@163.com.
  • 4 Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, Shaanxi Province, China; Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China. Electronic address: lc5kk96129@163.com.
  • 5 Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi Province, China. Electronic address: 15320021270@163.com.
  • 6 Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, Shaanxi Province, China; Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China. Electronic address: 974832718@qq.com.
  • 7 Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, Shaanxi Province, China; Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi Province, China. Electronic address: yan2128ts@med.nwu.edu.cn.
PMID: 39117135 DOI: 10.1016/j.exer.2024.110025
Abstract

Diabetic retinopathy (DR) is the leading cause of vision loss and blindness among working-age adults. Pericyte loss is an early pathological feature of DR. Under hyperglycemic conditions, Reactive Oxygen Species (ROS) production increases, leading to oxidative stress and subsequent mitochondrial dysfunction and Apoptosis. Dysfunctional pericyte can cause retinal vascular leakage, obliteration, and neovascularization. Glutaredoxin 2 (Grx2) is a mitochondrial glutathione-dependent oxidoreductase which protects cells against oxidative insults by safeguarding mitochondrial function. Whether Grx2 plays a protective role in diabetes-induced microvascular dysfunction remains unclear. Our findings revealed that diabetes-related stress reduced Grx2 expression in pericytes, but not in endothelial cells. Grx2 knock-in ameliorated diabetes-induced microvascular dysfunction in vivo DR models. Decreased Grx2 expression led to significant pericyte Apoptosis, and pericyte dysfunction, namely reduced pericyte recruitment towards endothelial cells and increased endothelial cell permeability. Conversely, upregulating Grx2 reversed these effects. Furthermore, Grx2 regulated pericyte Apoptosis by modulating complex I activity, which is crucial for pericyte mitochondrial function. Overall, our study uncovered a novel mechanism whereby high glucose inhibited Grx2 expression in vivo and in vitro. Grx2 downregulation exacerbated pericyte Apoptosis, pericyte dysfunction, and retinal vascular dysfunction by inactivating complex I and mediating mitochondrial dysfunction in pericytes.

Keywords

Apoptosis; Diabetic retinopathy; Endothelial cell; Glutaredoxin 2; Mitochondrial dysfunction; Pericyte.

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