Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 300384, Tianjin, China.
Department of Cardiology, Gansu Provincial Hospital, Lanzhou University, 730000, Lanzhou, Gansu Province, China.
Commun Biol. 2023 Aug 29;6(1):884. doi: 10.1038/s42003-023-05267-2.
Myopia is a major public health issue. However, interventional modalities for nonpathologic myopia are limited due to its complicated pathogenesis and the lack of precise targets. Here, we show that in guinea pig form-deprived myopia (FDM) and lens-induced myopia (LIM) models, the early initiation, phenotypic correlation, and stable maintenance of cochlin protein upregulation at the interface between retinal photoreceptors and retinal pigment epithelium (RPE) is identified by a proteomic analysis of ocular posterior pole tissues. Then, a microarray analysis reveals that cochlin upregulates the expression of the secreted frizzled-related protein 1 (SFRP1) gene in human RPE cells. Moreover, SFRP-1 elevates the intracellular Ca concentration and activates Ca/calmodulin-dependent protein kinase II (CaMKII) signaling in a simian choroidal vascular endothelial cell line, and elicits vascular endothelial cell dysfunction. Furthermore, genetic knockdown of the cochlin gene and pharmacological blockade of SFRP1 abrogates the reduced choroidal blood perfusion and prevents myopia progression in the FDM model. Collectively, this study identifies a novel signaling axis that may involve cochlin in the retina, SFRP1 in the RPE, and CaMKII in choroidal vascular endothelial cells and contribute to the pathogenesis of nonpathologic myopia, implicating the potential of cochlin and SFRP1 as myopia interventional targets.
近视是一个主要的公共卫生问题。然而，由于其复杂的发病机制和缺乏精确的靶点，对于非病理性近视的干预手段有限。在这里，我们通过对眼部后极组织的蛋白质组学分析，在豚鼠形觉剥夺性近视（FDM）和晶状体诱导性近视（LIM）模型中，发现了视网膜光感受器和视网膜色素上皮（RPE）之间的 cochlin 蛋白上调的早期发生、表型相关性和稳定维持。然后，微阵列分析显示 cochlin 在人 RPE 细胞中上调分泌卷曲相关蛋白 1（SFRP1）基因的表达。此外，SFRP-1 可提高猴脉络膜血管内皮细胞系中的细胞内 Ca 浓度，并激活 Ca/钙调蛋白依赖性蛋白激酶 II（CaMKII）信号通路，引发血管内皮细胞功能障碍。此外，Cochlin 基因的遗传敲低和 SFRP1 的药理学阻断可消除 FDM 模型中的脉络膜血液灌注减少，并阻止近视进展。总之，这项研究确定了一个新的信号轴，该信号轴可能涉及视网膜中的 cochlin、RPE 中的 SFRP1 和脉络膜血管内皮细胞中的 CaMKII，并有助于非病理性近视的发病机制，提示 cochlin 和 SFRP1 作为近视干预靶点的潜力。
