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低血糖症在糖尿病小鼠中促进内血液视网膜屏障的破坏和视网膜血管泄漏

Chuanyu Guo¹, Yueqi Niu¹, Xuemei Pan^1,2

¹Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Science translational medicine

|April 30, 2025

概括

低血糖会触发低氧诱导因素 (HIF),这些因素会在糖尿病视网膜病变中损害视网膜屏障 (BRB). 双重HIF抑制剂32-134D可以防止这种损伤,提供一种潜在的治疗策略.

科学领域:

眼科医生眼科眼科
内分泌学在内分泌学.
分子生物学分子生物学

背景情况:

血视网膜屏障 (BRB) 对视网膜健康至关重要,其分解有助于糖尿病视网膜病变的视力丧失.
低血糖症,通常是糖尿病管理的结果,可以破坏内部BRB (iBRB).

研究的目的:

调查低血糖诱导的转录因子,低氧诱导因子-1α (HIF-1α) 和HIF-2α在糖尿病视网膜病变中的作用.
评估双HIF抑制剂 (32-134D) 作为预防低血糖引起的BRB分解的治疗剂.

主要方法:

在低血糖条件下评估了小鼠视网膜中的HIF-1α和HIF-2α积累和HIF-依赖基因表达.
使用HIF-1α或HIF-2α的基因抑制和32-134D的药理抑制.
研究了32-134D对糖尿病小鼠和人类视网膜组织iBRB完整性和视网膜血管透性的影响.

主要成果:

低血糖诱导了HIF-1α和HIF-2α的积累,导致糖尿病小鼠中血管活性介质的表达增加和iBRB分解.
对HIFs的遗传抑制部分降低了低血糖引起的基因表达.
双重HIF抑制剂32-134D有效地阻断了人类和小鼠视网膜组织中的HIF-1α积累和HIF调节的基因表达,防止iBRB分解和血管过.

结论:

低血糖症通过激活HIF通路并损害BRB而加剧糖尿病视网膜病变.
通过32-134D进行双HIF抑制,在糖尿病患者中预防与低血糖症相关的视力损失具有前途.
这些发现支持对32-134D进行的临床研究,用于在血糖控制期间预防糖尿病视网膜病变的进展.

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