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.

慢性高血糖是一种破坏性因素，会导致糖尿病引起的视网膜和肾脏损伤。然而，高血糖驱动细胞凋亡的确切机制尚不完全清楚。在此，我们发现FOXD1（一种在视网膜和肾脏中特异性表达的FOX家族转录因子）调节BCL-2（细胞存活的主要调节因子）的转录。有趣的是，FOXD1 对高血糖条件有负面反应，其蛋白水平受到 TRIM21 介导的 K48 连接的多聚泛素化和随后的蛋白酶体降解的控制。 TRIM21-FOXD1-BCL-2 信号轴在糖尿病引起的小鼠视网膜和肾组织损伤期间显着活跃。此外，我们发现苦荞黄酮有效逆转FOXD1蛋白表达的下调，从而恢复BCL-2表达并促进视网膜和肾组织的存活。总之，我们确定了负责 BCL-2 表达的转录因子、高血糖触发细胞凋亡的信号轴 (TRM21-FOXD1-BCL-2) 以及治疗有害糖尿病并发症的潜在方法。