Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
Department of Ophthalmology, Qinghai Provincial People's Hospital, Xining 810007, Qinghai, China.
Toxicol Appl Pharmacol. 2024 Jan;482:116766. doi: 10.1016/j.taap.2023.116766. Epub 2023 Nov 22.
Pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) is an emerging player in diverse disorders. Our previous findings have documented that reducing PHLPP2 levels in cultured retinal ganglion cells protects against cellular damage caused by high glucose, indicating a possible link between PHLPP2 and diabetic retinopathy (DR). The present work was dedicated to the investigation of PHLPP2 in DR through in vivo experiments with rat models induced by intraperitoneal injection of streptozotocin. Compared to normal rats, the retinas of rats with DR exhibited a notable increase in the level of PHLPP2. The reduction of PHLPP2 levels in the retina was achieved by the intravitreal administration of adeno-associated viruses expressing specific shRNA targeting PHLPP2. Decreasing the expression of PHLPP2 ameliorated visual function impairment and improved the pathological changes of retina in DR rats. Moreover, decreasing the expression of PHLPP2 repressed the apoptosis, oxidative stress and proinflammatory response in the retinas of rats with DR. Reduction of PHLPP2 levels led to an increase in the levels of phosphorylated AKT and glycogen synthase kinase-3β (GSK-3β). Decreasing the expression of PHLPP2 resulted in increased activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which was reversed by suppressing AKT. Notably, the protective effect of reducing PHLPP2 on DR was eliminated when Nrf2 was restrained. These observations show that the down-regulation of PHLPP2 has protective effects on DR by preserving the structure and function of the retina by regulating the AKT-GSK-3β-Nrf2 signal cascade. Therefore, targeting PHLPP2 may hold promise in the treatment of DR.
PHLPP2 是一种具有 PH 结构域和亮氨酸丰富重复蛋白磷酸酶结构域的蛋白，它在多种疾病中发挥着重要作用。我们之前的研究结果表明，降低培养的视网膜神经节细胞中 PHLPP2 的水平可以防止高葡萄糖引起的细胞损伤，这表明 PHLPP2 与糖尿病视网膜病变（DR）之间可能存在联系。本研究通过腹腔注射链脲佐菌素诱导的大鼠模型进行体内实验，致力于研究 PHLPP2 在 DR 中的作用。与正常大鼠相比，DR 大鼠的视网膜中 PHLPP2 的水平显著升高。通过玻璃体腔注射表达针对 PHLPP2 的特异性 shRNA 的腺相关病毒来降低视网膜中 PHLPP2 的水平。降低 PHLPP2 的表达水平改善了 DR 大鼠的视觉功能障碍，并改善了视网膜的病理变化。此外，降低 PHLPP2 的表达水平抑制了 DR 大鼠视网膜中的细胞凋亡、氧化应激和促炎反应。降低 PHLPP2 的水平导致磷酸化 AKT 和糖原合酶激酶-3β（GSK-3β）的水平增加。降低 PHLPP2 的表达水平导致核因子红细胞 2 相关因子 2（Nrf2）的激活增加，而 AKT 的抑制可逆转这种增加。值得注意的是，当抑制 Nrf2 时，降低 PHLPP2 对 DR 的保护作用被消除。这些观察结果表明，通过调节 AKT-GSK-3β-Nrf2 信号级联来保护视网膜的结构和功能，下调 PHLPP2 对 DR 具有保护作用。因此，靶向 PHLPP2 可能为 DR 的治疗提供新的策略。
