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

Wenwen Cheng1, Cifeng Cai1, Yifan Xu1

  • 1College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China.

Cell Death & Disease
|December 13, 2023
PubMed

Insights

High blood sugar (hyperglycaemia) triggers cell death in the eyes and kidneys. Researchers identified a pathway involving TRIM21, FOXD1, and BCL-2 that drives this damage, with tartary buckwheat flavonoids showing therapeutic potential.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Endocrinology

Background:

  • Chronic hyperglycemia is a primary cause of diabetic complications, leading to retinal and kidney damage.
  • The exact mechanisms driving hyperglycaemia-induced apoptotic cell death remain incompletely understood.
  • Understanding these pathways is crucial for developing effective treatments for diabetic nephropathy and retinopathy.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying hyperglycaemia-induced apoptosis in retinal and renal tissues.
  • To identify key regulatory factors and signaling pathways involved in diabetic complications.
  • To explore potential therapeutic interventions targeting these pathways.

Main Methods:

  • Investigated the role of FOXD1 (a transcription factor) in regulating BCL-2 (a cell survival gene) under hyperglycaemic conditions.
  • Examined the regulation of FOXD1 protein levels via TRIM21-mediated ubiquitination and proteasomal degradation.
  • Assessed the activity of the TRIM21-FOXD1-BCL-2 signaling axis in murine models of diabetic retinal and renal damage.
  • Evaluated the therapeutic effects of tartary buckwheat flavonoids on this pathway and tissue survival.

Main Results:

  • FOXD1 directly regulates the transcription of BCL-2, a key factor in cell survival.
  • Hyperglycaemic conditions lead to decreased FOXD1 protein levels through TRIM21-mediated degradation.
  • The TRIM21-FOXD1-BCL-2 signaling axis is implicated in diabetic damage to the retina and kidney.
  • Tartary buckwheat flavonoids effectively reversed FOXD1 downregulation, restored BCL-2 expression, and promoted tissue survival.

Conclusions:

  • Identified FOXD1 as a critical transcription factor for BCL-2 expression in the context of diabetic complications.
  • Uncovered the TRIM21-FOXD1-BCL-2 signaling axis as a key mediator of hyperglycaemia-induced apoptosis.
  • Demonstrated the potential of tartary buckwheat flavonoids as a therapeutic strategy for mitigating diabetic retinal and renal damage.

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