Institute of Cytology and Genetics (ICG), Siberian Branch of Russian Academy of Sciences (SB RAS), 10 Akad. Lavrentieva Avenue, 630090 Novosibirsk, Russia.
Int J Mol Sci. 2023 Jul 18;24(14):11586. doi: 10.3390/ijms241411586.
Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. Age is the greatest risk factor for AMD but the underlying mechanism remains unascertained, resulting in a lack of effective therapies. Growing evidence shows that dysregulation of the p38 MAPK signaling pathway (SP) contributes to aging and neurodegenerative diseases; however, information about its alteration in the retina with age and during AMD development is limited. To assess the contribution of alterations in p38 MAPK signaling to AMD, we compared age-associated changes in p38 MAPK SP activity in the retina between Wistar rats (control) and OXYS rats, which develop AMD-like retinopathy spontaneously. We analyzed changes in the mRNA levels of genes of this SP in the retina (data of RNA-seq) and evaluated the phosphorylation/activation of key kinases using Western blotting at different stages of AMD-like pathology including the preclinical stage. p38 MAPK SP activity increased in the retinas of healthy Wistar rats with age. The manifestation and dramatic progression of AMD-like pathology in OXYS rats was accompanied by hyperphosphorylation of p38 MAPK and MK2 as key p38 MAPK SP kinases. Retinopathy progression co-occurred with the enhancement of p38 MAPK-dependent phosphorylation of CryaB at Ser59 in the retina.
年龄相关性黄斑变性（AMD）是全球范围内导致不可逆性视力损害的主要原因。年龄是 AMD 的最大风险因素，但潜在机制仍未确定，导致缺乏有效的治疗方法。越来越多的证据表明，p38 MAPK 信号通路（SP）的失调与衰老和神经退行性疾病有关；然而，关于其在视网膜中的改变与年龄和 AMD 发展过程中的信息有限。为了评估 p38 MAPK 信号转导改变对 AMD 的贡献，我们比较了 Wistar 大鼠（对照组）和 OXYS 大鼠（自发发生 AMD 样视网膜病变）之间视网膜中 p38 MAPK SP 活性与年龄相关的变化。我们分析了该 SP 在视网膜中的基因的 mRNA 水平的变化（RNA-seq 数据），并在包括临床前阶段在内的不同 AMD 样病理阶段使用 Western blot 评估了关键激酶的磷酸化/激活。随着年龄的增长，健康的 Wistar 大鼠视网膜中的 p38 MAPK SP 活性增加。OXYS 大鼠的 AMD 样病理表现和急剧进展伴随着 p38 MAPK 和 MK2 的过度磷酸化，这是 p38 MAPK SP 的关键激酶。视网膜病变的进展与视网膜中 CryaB 在 Ser59 处的 p38 MAPK 依赖性磷酸化增强同时发生。
