Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats

Xinyi Ding; Zhongcui Sun; Yue Guo; Wenyi Tang; Qinmeng Shu; Gezhi Xu

doi:10.21037/atm-22-2204

Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats

Ann Transl Med. 2023 Mar 15;11(5):197. doi: 10.21037/atm-22-2204. Epub 2023 Feb 28.

Authors

Xinyi Ding^{1

2

3}, Zhongcui Sun^{1

2

3}, Yue Guo^{1

2

3}, Wenyi Tang^{1

2

3}, Qinmeng Shu^{1

2

3}, Gezhi Xu^{1

2

3}

Affiliations

¹ Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, China.
³ Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, Shanghai, China.

Abstract

Background: To determine the anti-inflammatory effects of IMD-0354, a specific NF-κB blocker, on glial cells in rats with streptozotocin (STZ)-induced diabetic retinopathy (DR).

Methods: The following four groups of rats were used: control, control + IMD-0354, STZ, and STZ + IMD-0354. After six weeks of STZ injection, diabetic rats and nondiabetic control rats received IMD-0354 (30 mg/kg) or an equal volume of 4% dimethyl sulfoxide (DMSO) in phosphate-buffered saline intraperitoneally for six consecutive weeks. The following four groups of primary rat retinal microglia and Müller cells were used: control (5 mM), control + IMD-0354, high glucose (20 mM), and high glucose + IMD-0354. The effects of IMD-0354 on nuclear factor-κB (NF-κB) activation, oxidative stress strength, expression of inflammatory cytokines and VEGF (vascular endothelial growth factor), activation of glial cells, and apoptosis of neuron cells were evaluated by immunohistochemistry, oxidative stress assays, western blot, enzyme linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining respectively.

Results: Nuclear translocation of NF-κB was markedly increased in diabetic rat retina and high glucose treated glial cells. Systemic administration of IMD-0354 significantly inhibited NF-κB activation in both diabetic rat retina and high glucose treated glial cells, ameliorated oxidative injury, inflammatory responses, VEGF production and glial cell activation, and protected neurons from apoptosis.

Conclusions: Our findings indicated that NF-κB activation is acritical step in the abnormal reactivity of glial cells in STZ-induced diabetic rats. Inhibition effect of IMD-0354 on NF-κB activation may represent a promising therapeutic strategy for DR via a variety of mechanisms, including inflammation reduction and glial cells regulation.

Keywords: IMD-0354; Müller cells; diabetic retinopathy; microglia; nuclear factor-κB (NF-κB).