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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Published inCell death & disease Vol. 14; no. 12; pp. 825 - 14
Main Authors Cheng, Wenwen, Cai, Cifeng, Xu, Yifan, Xiao, Xueqi, Shi, Tiantian, Liao, Yueling, Wang, Xiaoyi, Chen, Shasha, Zhou, Meiliang, Liao, Zhiyong
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 13.12.2023
Springer Nature B.V
Nature Publishing Group
Subjects
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Antibodies
Apoptosis
Bcl-2 protein
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell death
Cell survival
Diabetes
Diabetes mellitus
Flavonoids
Hyperglycemia
Immunology
Kidneys
Life Sciences
Proteasomes
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.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06355-1