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TRIM25 inhibition attenuates inflammation, senescence, and oxidative stress in microvascular endothelial cells induced by hyperglycemia

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Abstract

Purposes

This work aimed to assess the possible role of TRIM25 in regulating hyperglycemia-induced inflammation, senescence, and oxidative stress in retinal microvascular endothelial cells, all of which exert critical roles in the pathological process of diabetic retinopathy.

Methods

The effects of TRIM25 were investigated using streptozotocin-induced diabetic mice, human primary retinal microvascular endothelial cells cultured in high glucose, and adenoviruses for TRIM25 knockdown and overexpression. TRIM25 expression was evaluated by western blot and immunofluorescence staining. Inflammatory cytokines were detected by western blot and quantitative real-time PCR. Cellular senescence level was assessed by detecting senescent marker p21 and senescence‐associated‐β‐galactosidase activity. The oxidative stress state was accessed by detecting reactive oxygen species and mitochondrial superoxide dismutase.

Results

TRIM25 expression is elevated in the endothelial cells of the retinal fibrovascular membrane from diabetic patients compared with that of the macular epiretinal membrane from non-diabetic patients. Moreover, we have also observed a significant increase in TRIM25 expression in diabetic mouse retina and retinal microvascular endothelial cells under hyperglycemia. TRIM25 knockdown suppressed hyperglycemia-induced inflammation, senescence, and oxidative stress in human primary retinal microvascular endothelial cells while TRIM25 overexpression further aggregates those injuries. Further investigation revealed that TRIM25 promoted the inflammatory responses mediated by the TNF-α/NF-κB pathway and TRIM25 knockdown improved cellular senescence by increasing SIRT3. However, TRIM25 knockdown alleviated the oxidative stress independent of both SIRT3 and mitochondrial biogenesis.

Conclusion

Our study proposed TRIM25 as a potential therapeutic target for the protection of microvascular function during the progression of diabetic retinopathy.

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Funding

This work was supported by the Science and Technology Research Project of Songjiang District [grant number 2020SJ300]; the National Key R&D Program of China [grant numbers 2016YFC0904800, 2019YFC0840607]; National Science and Technology Major Project of China [grant number 2017ZX09304010]; and Shanghai Key Clinical Specialty.

Author information

Author notes

  1. Dandan Sun and Shenping Li contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Dandan Sun, Shenping Li, Shimei Chen, Shuchang Zhang, Qing Gu, Yinchen Shen, Fang Wei & Ning Wang

  2. National Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseaseShanghai Engineering Center for Visual Science and Photo MedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China

    Dandan Sun, Shenping Li, Shimei Chen, Shuchang Zhang, Qing Gu, Yinchen Shen, Fang Wei & Ning Wang

Authors
  1. Dandan Sun
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Contributions

DS, NW, and FW designed this study. DS and SL executed the experiments. NW, SC, and YS collected the human specimens, carried out experiments, and analyzed data. DS and SZ maintained the mice. NW, FW, and QG provided resources, supervised the experiments, and participated in the data analyses. DS, FW, and NW wrote the article with input from all authors. All authors proofread the manuscript.

Corresponding authors

Correspondence to Fang Wei or Ning Wang.

Ethics declarations

Ethics approval

Animals were treated in accordance with the ARRIVE guidelines and the National Research Council’s Guide for the Care and Use of Laboratory Animals and approved by the Ethics committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (reference number: 2019-A049-01).

Human samples were collected with informed consent following the guidelines of the Helsinki Declaration. This study was approved by the Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (reference number: 2020SQ100).

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The authors declare no competing interests.

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Sun, D., Li, S., Chen, S. et al. TRIM25 inhibition attenuates inflammation, senescence, and oxidative stress in microvascular endothelial cells induced by hyperglycemia. Graefes Arch Clin Exp Ophthalmol 262, 81–91 (2024). https://doi.org/10.1007/s00417-023-06160-8

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