Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
Invest Ophthalmol Vis Sci. 2023 Jun 1;64(7):13. doi: 10.1167/iovs.64.7.13.
Diabetic retinopathy (DR) is a significant cause of blindness. Most research around DR focus on late-stage developments rather than early changes such as early endothelial dysfunction. Endothelial-to-mesenchymal transition (EndMT), an epigenetically regulated process whereby endothelial cells lose endothelial characteristics and adopt mesenchymal-like phenotypes, contributes to early endothelial changes in DR. The epigenetic regulator microRNA 9 (miR-9) is suppressed in the eyes during DR. MiR-9 plays a role in various diseases and regulates EndMT-related processes in other organs. We investigated the role miR-9 plays in glucose-induced EndMT in DR.
We examined the effects of glucose on miR-9 and EndMT using human retinal endothelial cells (HRECs). We then used HRECs and an endothelial-specific miR-9 transgenic mouse line to investigate the effect of miR-9 on glucose-induced EndMT. Finally, we used HRECs to probe the mechanisms through which miR-9 may regulate EndMT.
We found that miR-9 inhibition was both necessary and sufficient for glucose-induced EndMT. Overexpression of miR-9 prevented glucose-induced EndMT, whereas suppressing miR-9 caused glucose-like EndMT changes. We also found that preventing EndMT with miR-9 overexpression improved retinal vascular leakage in DR. Finally, we showed that miR-9 regulates EndMT at an early stage by regulating EndMT-inducing signals such as proinflammatory and TGF-β pathways.
We have shown that miR-9 is an important regulator of EndMT in DR, potentially making it a good target for RNA-based therapy in early DR.
糖尿病视网膜病变（DR）是失明的一个重要原因。大多数关于 DR 的研究都集中在晚期发展上，而不是早期变化，如早期内皮功能障碍。内皮到间充质转化（EndMT）是一个受表观遗传调控的过程，在此过程中，内皮细胞失去内皮特征，采用间充质样表型，这有助于 DR 中的早期内皮变化。表观遗传调节剂 microRNA 9（miR-9）在 DR 期间在眼睛中受到抑制。miR-9 在各种疾病中发挥作用，并调节其他器官中的 EndMT 相关过程。我们研究了 miR-9 在葡萄糖诱导的 DR 中的 EndMT 中的作用。
我们使用人视网膜内皮细胞（HRECs）检查葡萄糖对 miR-9 和 EndMT 的影响。然后，我们使用 HRECs 和内皮特异性 miR-9 转基因小鼠系来研究 miR-9 对葡萄糖诱导的 EndMT 的影响。最后，我们使用 HRECs 来探究 miR-9 可能调节 EndMT 的机制。
我们发现 miR-9 的抑制对于葡萄糖诱导的 EndMT 是必要和充分的。miR-9 的过表达可防止葡萄糖诱导的 EndMT，而抑制 miR-9 则导致葡萄糖样 EndMT 变化。我们还发现，通过 miR-9 的过表达预防 EndMT 可改善 DR 中的视网膜血管渗漏。最后，我们表明，miR-9 通过调节促炎和 TGF-β 等诱导 EndMT 的信号来调节 EndMT 的早期阶段。
我们已经表明，miR-9 是 DR 中 EndMT 的重要调节剂，这使其有可能成为早期 DR 中基于 RNA 的治疗的良好靶标。
