Nrf2对线粒体稳态的调节在氢治疗糖尿病视网膜病变早期节细胞损伤中的作用机制

Diabetic retinopathy (DR) is the most common complication of diabetes. The diagnosis and treatment of DR are only based on the retinal vascular lesions, and clinical intervention is almost blank before retinal vasculopathy occurs. The existence of “metabolic memory” of hyperglycemia suggests that some pathological changes before the occurrence of retinal vasculopathy is the key link that leads DR into a sustainable and irreversible development. Research have showed that diabetic retinal neurodegeneration is characteristic of DR at early stage before retinal vasculopathy, which is featured and probably initiated by retinal ganglion cells damage, and mitochondria dysfunction play a key role in ganglion cells damage induced by high glucose. Our previous study have found that hydrogen treatment have both short-time and long-time protective effect through selective anti-oxidative mechanism and activation of Nfr2 and its downstream intrinsic anti-oxidative system respectively. In addition, hydrogen treatment could protect the ganglion cells damage at early stage of DR through mitochondrial function improvement. Given that Nrf2 can regulate mitochondrial biogenesis through multiple levels, which closely relates to mitochondrial dynamics change and autophagy and is the major link in mitochondrial homeostasis. We intend to confirm that Nrf2’s regulation on mitochondrial homeostasis is the main mechanism of hydrogen treatment in protection of retinal ganglion cells at early stage of DR, aiming to provide valuable direction and theoretical basis for future clinical intervention of DR at early stage.

糖尿病视网膜病变（DR）是糖尿病最常见的并发症。临床对DR的诊治均以视网膜的血管损伤为依据，在视网膜出现血管病变前的眼科干预几乎空白。高血糖“代谢记忆”的存在提示：在视网膜血管病变发生之前的某种病理改变是导致DR进入不可逆病理进展的关键环节。研究显示，视网膜神经退行性变是DR早期先于血管病变的特征性改变，其主要特征和可能的启动环节是节细胞损伤，而线粒体在此过程中发挥关键作用。我们前期研究发现，氢治疗分别通过选择性抗氧化机制和激活Nfr2及其下游内源性抗氧化系统发挥对DR的短时和长时保护作用；此外，氢治疗能通过对线粒体功能的改善保护DR早期的节细胞损伤。鉴于Nrf2能直接调控线粒体的生物合成，而线粒体生物合成与其动力学改变和自噬关系密切，是线粒体稳态的中心环节；因而，我们拟证实Nrf2对线粒体稳态的调控是氢治疗DR早期节细胞损伤的主要机制，以期为未来DR的早期治疗提供新的方向和理论依据。

糖尿病视网膜病变（DR）是糖尿病最常见的并发症。临床对DR的诊治均以视网膜的血管损伤为依据，在视网膜出现血管病变前的眼科干预几乎空白。高血糖“代谢记忆”的存在提示：在视网膜血管病变发生之前的某种病理改变是导致DR进入不可逆病理进展的关键环节。研究显示，视网膜神经退行性变是DR早期先于血管病变的特征性改变，其主要特征和可能的启动环节是节细胞损伤，而线粒体在此过程中发挥关键作用。我们的研究发现氢吸入治疗可通过上调DR早期视网膜组织中的核因子E2相关因子2（Nrf2）转录活性及其下游保护性靶基因表达，从而显著抑制小鼠DR早期视网膜神经元的线粒体途径凋亡进程以发挥神经保护效应；增加高氢吸入治疗时间，未能显著增强其神经保护效应。我们对氢治疗DR早期视网膜神经退行性变保护作用及其分子机制的研究，不仅有助于深化对DR引起的早期神经损伤机制的了解，也为未来DR早期视网膜神经退行性变的治疗提供新思路。此外，抗血管生长因子（VEGF）已成为许多视网膜疾病最常见的治疗手段，其中包括增殖性DR，但其需要多次眼内注射，并发症风险相对较大。我们利用框架核酸拓扑适配体（FNAs）的精确形貌构建能力与定点拓扑修饰潜力，将抗VEGF核酸适体通过结膜下注射的方式递送至眼后段病变区域，以抑制增殖性DR诱发眼底血管增生，结果显示基于FNAs的抗VEGF药物输运体系能够穿透眼部的多个组织，将抗VEGF药物递送至眼后段视网膜血管，为实现安全、有效、无创的眼底病抗VEGF治疗提供了新策略和新依据。