Xu Ning, Li Zongyuan, Zeng Xiangwen, Jiang Yilin, Sun Tunan, Liu Shuyu, Li Na, Li Zhao, Huang Yifei, Wang Liqiang
Medical School of Chinese People's Liberation Army, Beijing, China.
Department of Ophthalmology, The Third Medical Center, General Hospital of Chinese People's Liberation Army, Beijing, China.
Cell Death Dis. 2025 May 29;16(1):423. doi: 10.1038/s41419-025-07742-6.
Ischemia-reperfusion (I/R) injury is associated with a variety of retinal diseases, resulting in loss of the number of ganglion cells (RGCs), retinal structural disorders, and retinal dysfunction. The Reelin protein is an important regulator of neuronal migration and synaptogenesis, and the Reln signaling pathway plays an essential role in regulating the targeted projection of RGC dendrites and neuronal survival, which has not been reported in retinal I/R injury. The aim of this study was to investigate the expression, role and mechanism of Reln in retinal I/R injury. By establishing Reln-CreERT2 mTmG transgenic mice, it was observed that the expression of Reln initially decreased and then increased after retinal I/R injury. After supplementing exogenous Reelin protein and adeno-associated virus (AAV)-targeted regulation of Reln in vivo, morphological and functional experiments demonstrated its effectiveness in protecting RGCs survival, maintaining morphological integrity of the retina, and inhibiting post-injury retinal dysfunction. Furthermore, integrin β1 (Itgb1) was identified as the main receptor through which Reelin exerts neuroprotective effects while regulating retinal I/R injury repair through the Dab1-PI3K-Akt pathway. These findings provide evidence supporting Reln pathway's role in maintaining retinal homeostasis and facilitating injury repair. Moreover, these findings have significant implications for identifying new targets for preventing and treating various retinal diseases.
缺血再灌注（I/R）损伤与多种视网膜疾病相关，可导致神经节细胞（RGCs）数量减少、视网膜结构紊乱和视网膜功能障碍。Reelin蛋白是神经元迁移和突触形成的重要调节因子，Reln信号通路在调节RGC树突的靶向投射和神经元存活中起重要作用，而这在视网膜I/R损伤中尚未见报道。本研究旨在探讨Reln在视网膜I/R损伤中的表达、作用及机制。通过建立Reln-CreERT2 mTmG转基因小鼠，观察到视网膜I/R损伤后Reln的表达先降低后升高。在体内补充外源性Reelin蛋白和腺相关病毒（AAV）靶向调节Reln后，形态学和功能实验证明其在保护RGCs存活、维持视网膜形态完整性以及抑制损伤后视网膜功能障碍方面的有效性。此外，整合素β1（Itgb1）被确定为Reelin发挥神经保护作用的主要受体，同时通过Dab1-PI3K-Akt途径调节视网膜I/R损伤修复。这些发现为Reln通路在维持视网膜稳态和促进损伤修复中的作用提供了证据。此外，这些发现对于确定预防和治疗各种视网膜疾病的新靶点具有重要意义。
