Zhou Liqiong, Zhang Chunhui, Cheng Quan, Ma Minjun, Fan Xinyu, Han Yuanhui, Zha Xu, Zhang Yuanping
Ophthalmology Department, The Second Affiliated Hospital of Kunming Medical University, No. 374 Dianmian Avenue, Wuhua District, 650000, Kunming, China.
J Mol Histol. 2025 Jun 4;56(3):183. doi: 10.1007/s10735-025-10458-8.
Neurodegeneration in early-stage diabetes retinopathy (DR) is mainly caused by the loss of retinal ganglion cells (RGCs), and high glucose-treated cell pyroptosis contributes to an important cause. However, the detailed molecular regulatory mechanism has not yet been thoroughly examined. In this study, primary mouse RGCs were stimulated with different concentrations of glucose, and mouse was intraperitoneally injected with streptozotocin (STZ) to construct DR model in vitro and in vivo. We found that compared to normal controls, RNA binding motif protein 15 (RBM15) was significantly upregulated in high glucose-treated RGCs and STZ-induced mice. RBM15 silence restored cell viability and inhibited cell apoptosis and cell death in high glucose-triggered RGCs. In parallel, RBM15 knockdown distinctly improved pathological damage such as thinning of retinal tissue thickness and loss of RGCs in STZ-modeling mice. Interestingly, the production of inflammatory cytokines and the expression of Cleaved caspase-1, NLRP3 and GSDMD-N were significantly reduced by RBM15 silence in vivo and in vitro. Mechanistically, RBM15 bound to kruppel like factor 6 (KLF6) mRNA to promote m6A modification and stabilize KLF6 mRNA, upregulating KLF6 expression in model cells and model mice retinal tissues. KLF6 overexpression increased the production of inflammatory cytokines and the expression of proteins related to pyroptosis, reversing the protective effects of RBM15 silence in high glucose-treated RGCs and diabetic retina. In conclusion, RBM15 is upregulated by high glucose, and stabilizes KLF6 mRNA to activate NLRP3-mediated pyroptosis pathway, exacerbating inflammation and apoptosis of RGCs and accelerating the progression of DR.
早期糖尿病视网膜病变（DR）中的神经退行性变主要由视网膜神经节细胞（RGCs）的丧失引起，高糖处理的细胞焦亡是一个重要原因。然而，详细的分子调控机制尚未得到充分研究。在本研究中，用不同浓度的葡萄糖刺激原代小鼠RGCs，并给小鼠腹腔注射链脲佐菌素（STZ）以在体外和体内构建DR模型。我们发现，与正常对照相比，RNA结合基序蛋白15（RBM15）在高糖处理的RGCs和STZ诱导的小鼠中显著上调。RBM15沉默恢复了细胞活力，并抑制了高糖触发的RGCs中的细胞凋亡和细胞死亡。同时，RBM15敲低明显改善了STZ建模小鼠的病理损伤，如视网膜组织厚度变薄和RGCs丢失。有趣的是，体内和体外RBM15沉默均显著降低了炎性细胞因子的产生以及Cleaved caspase-1、NLRP3和GSDMD-N的表达。机制上，RBM15与克鲁ppel样因子6（KLF6）mRNA结合，促进m6A修饰并稳定KLF6 mRNA，上调模型细胞和模型小鼠视网膜组织中KLF6的表达。KLF6过表达增加了炎性细胞因子的产生和与焦亡相关的蛋白质的表达，逆转了RBM15沉默在高糖处理的RGCs和糖尿病视网膜中的保护作用。总之，RBM15被高糖上调，并稳定KLF6 mRNA以激活NLRP3介导的焦亡途径，加剧RGCs的炎症和凋亡，加速DR的进展。
