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Background <p>Diabetic retinopathy (DR) affects vision and can even cause blindness. Kruppel-like factor 7 (KLF7) takes part in high-glucose (HG)-prompted retinal pigment epithelial cell (RPE) apoptosis in vitro, the molecular mechanisms of KLF7-mediated DR pathogenesis are poorly studied.</p> Methods <p>HG-challenged RPEs were used as a model for DR in vitro. Cell viability, proliferation, apoptosis, and inflammation were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, 5-ethynyl-2’-deoxyuridine, flow cytometry, and TUNEL assays. Oxidative stress damage was determined by detection of ROS and MDA. The interaction between KLF7 and forkhead box protein O4 (FOXO4) was estimated by chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays. The toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway was assessed by western blot and the NF-κB inhibitor BAY 11-7085.</p> Results <p>HG induced up-regulation of KLF7 in RPEs, and KLF7 silencing weakened HG-induced RPE apoptosis, inflammation, and oxidative stress damage. FOXO4 activated the transcription of KLF7, and FOXO4 silencing demonstrated the same function as KLF7 knockdown in HG-challenged RPEs. Moreover, KLF7 down-regulation reversed FOXO4 overexpression-mediated promoting effect on HG-induced RPE injury. Interestingly, FOXO4 activated the TLR4/MyD88/NF-κB pathway by KLF7, and BAY 11-7085 overturned KLF7 elevation-mediated effects on HG-induced RPE injury.</p> Conclusion <p>FOXO4 participated in HG-induced RPE injury via activation of the TLR4/MYD88/NF-κB pathway by enhancing the transcription of KLF7, supporting that FOXO4 and KLF7 as potential targets for DR treatment.</p>

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FOXO4 Facilitates Diabetic Retinopathy by Mediating KLF7 Transcription and Affecting the TLR4/MyD88/NF-κB Pathway

  • 期刊论文

  • 发表日期：

    2025年11月13日

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  • Wenwen Yang,
  • Guangjun Xu,
  • Dengxue Wang

摘要

Background

Diabetic retinopathy (DR) affects vision and can even cause blindness. Kruppel-like factor 7 (KLF7) takes part in high-glucose (HG)-prompted retinal pigment epithelial cell (RPE) apoptosis in vitro, the molecular mechanisms of KLF7-mediated DR pathogenesis are poorly studied.

Methods

HG-challenged RPEs were used as a model for DR in vitro. Cell viability, proliferation, apoptosis, and inflammation were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, 5-ethynyl-2’-deoxyuridine, flow cytometry, and TUNEL assays. Oxidative stress damage was determined by detection of ROS and MDA. The interaction between KLF7 and forkhead box protein O4 (FOXO4) was estimated by chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays. The toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway was assessed by western blot and the NF-κB inhibitor BAY 11-7085.

Results

HG induced up-regulation of KLF7 in RPEs, and KLF7 silencing weakened HG-induced RPE apoptosis, inflammation, and oxidative stress damage. FOXO4 activated the transcription of KLF7, and FOXO4 silencing demonstrated the same function as KLF7 knockdown in HG-challenged RPEs. Moreover, KLF7 down-regulation reversed FOXO4 overexpression-mediated promoting effect on HG-induced RPE injury. Interestingly, FOXO4 activated the TLR4/MyD88/NF-κB pathway by KLF7, and BAY 11-7085 overturned KLF7 elevation-mediated effects on HG-induced RPE injury.

Conclusion

FOXO4 participated in HG-induced RPE injury via activation of the TLR4/MYD88/NF-κB pathway by enhancing the transcription of KLF7, supporting that FOXO4 and KLF7 as potential targets for DR treatment.