The TRIM21-FOXD1-BCL-2 axis underlies hyperglycaemic cell death and diabetic tissue damage

Chronic hyperglycaemia is a devastating factor that causes diabetes-induced damage to the retina and kidney. However, the precise mechanism by which hyperglycaemia drives apoptotic cell death is incompletely known. Herein, we found that FOXD1, a FOX family transcription factor specifically expressed...

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Bibliographic Details
Published in:Cell death & disease 2023-12, Vol.14 (12), p.825-825, Article 825
Main Authors: Cheng, Wenwen, Cai, Cifeng, Xu, Yifan, Xiao, Xueqi, Shi, Tiantian, Liao, Yueling, Wang, Xiaoyi, Chen, Shasha, Zhou, Meiliang, Liao, Zhiyong
Format: Article
Language:English
Subjects:
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Animals
Antibodies
Apoptosis
Apoptosis - genetics
Bcl-2 protein
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell death
Cell survival
Diabetes
Diabetes mellitus
Diabetes Mellitus - genetics
Flavonoids
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Hyperglycemia
Hyperglycemia - genetics
Immunology
Kidneys
Life Sciences
Mice
Proteasomes
Proto-Oncogene Proteins c-bcl-2 - genetics
Retina
Transcription factors
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Summary:Chronic hyperglycaemia is a devastating factor that causes diabetes-induced damage to the retina and kidney. However, the precise mechanism by which hyperglycaemia drives apoptotic cell death is incompletely known. Herein, we found that FOXD1, a FOX family transcription factor specifically expressed in the retina and kidney, regulated the transcription of BCL-2, a master regulator of cell survival. Intriguingly, the protein level of FOXD1, which responded negatively to hyperglycaemic conditions, was controlled by the TRIM21-mediated K48-linked polyubiquitination and subsequent proteasomal degradation. The TRIM21-FOXD1-BCL-2 signalling axis was notably active during diabetes-induced damage to murine retinal and renal tissues. Furthermore, we found that tartary buckwheat flavonoids effectively reversed the downregulation of FOXD1 protein expression and thus restored BCL-2 expression and facilitated the survival of retinal and renal tissues. In summary, we identified a transcription factor responsible for BCL-2 expression, a signalling axis (TRM21-FOXD1-BCL-2) underlying hyperglycaemia-triggered apoptosis, and a potential treatment for deleterious diabetic complications.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06355-1