Wu Ting, Guo Yin-Kun, Long Fang-Yi, Duan Shang-Shang, Li Xiao-Hong, Liu Guo, Du Jun-Rong, Yan Nai-Hong
Department of Pharmacology, West China School of Pharmacy, Department of Radiology, West China Second Hospital, Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care, Chengdu, 610032, Sichuan, China.
Sci Rep. 2025 Sep 26;15(1):33103. doi: 10.1038/s41598-025-17122-x.
Diabetic retinopathy (DR) is a key eye-related complication linked to diabetes. Chronic inflammation is recognized as the main pathological mechanism leading to retinal damage during the onset and progression of DR. Alpha kinase 1 (ALPK1), a member of a recently discovered serine/threonine protein kinase family, is associated with the onset of multiple inflammatory conditions. Dominant mutations in the ALPK1 gene can result in a rare genetic disorder, known as ROSAH syndrome, which is characterized by ocular inflammatory responses. The role of ALPK1 in DR remains largely unclear and necessitates additional research for a better understanding. Therefore, investigating the function and underlying mechanisms of ALPK1 in DR is highly necessary. In this research, ALPK1 expression and inflammatory cytokines levels were examined in db/db diabetic mice. Additionally, BV2 mouse microglial cells were utilized to establish a hypoxia model that mimicked DR conditions, and the influence of ALPK1 knockdown on these conditions was assessed. The effects of ALPK1 knockdown on retinal damage in db/db diabetic mice were also evaluated. In db/db mice, our findings indicated a decrease in retinal cell numbers and irregular retinal blood vessel formation, along with increased levels of ALPK1 and inflammatory markers TNF-α, IL-1β, IL-6, and IL-18. ALPK1 expression was found to be associated with the TIFA/TRAF6 signaling pathway. Knockdown of ALPK1 was shown to reduce the levels of these inflammatory cytokines, diminish GSDMD-mediated pyroptosis signaling, and mitigate the DR-induced retinal cell damage in BV2 cells. Furthermore, reducing ALPK1 expression in the retinas of db/db diabetic mice was observed to slow down retinal cell degeneration and alleviate microvascular injury within the retina. This research indicated the substantial involvement of ALPK1 in the diabetic retinopathy-linked inflammatory cascade and cell pyroptosis. Targeting the ALPK1 signaling pathway could open avenues for novel therapeutic strategies to manage DR.
糖尿病视网膜病变（DR）是一种与糖尿病相关的关键眼部并发症。慢性炎症被认为是DR发生和发展过程中导致视网膜损伤的主要病理机制。α激酶1（ALPK1）是最近发现的丝氨酸/苏氨酸蛋白激酶家族的成员，与多种炎症性疾病的发生有关。ALPK1基因的显性突变可导致一种罕见的遗传性疾病，称为ROSAH综合征，其特征为眼部炎症反应。ALPK1在DR中的作用在很大程度上仍不清楚，需要进一步研究以更好地理解。因此，研究ALPK1在DR中的功能和潜在机制非常必要。在本研究中，检测了db/db糖尿病小鼠中ALPK1的表达和炎性细胞因子水平。此外，利用BV2小鼠小胶质细胞建立了模拟DR条件的缺氧模型，并评估了敲低ALPK1对这些条件的影响。还评估了敲低ALPK1对db/db糖尿病小鼠视网膜损伤的影响。在db/db小鼠中，我们的研究结果表明视网膜细胞数量减少和视网膜血管形成不规则，同时ALPK1水平以及炎性标志物TNF-α、IL-1β、IL-6和IL-18升高。发现ALPK1表达与TIFA/TRAF6信号通路相关。敲低ALPK1可降低这些炎性细胞因子的水平，减少GSDMD介导的细胞焦亡信号，并减轻DR诱导的BV2细胞中的视网膜细胞损伤。此外，观察到降低db/db糖尿病小鼠视网膜中ALPK1的表达可减缓视网膜细胞变性并减轻视网膜内的微血管损伤。本研究表明ALPK1大量参与了与糖尿病视网膜病变相关的炎症级联反应和细胞焦亡。靶向ALPK1信号通路可为管理DR的新治疗策略开辟道路。
