Duh Elia J, Xu Zhenhua, Cho Hongkwan, Wu Shirley, Schubert William, Terjung Carsten, Baschiera Fabio, Zhou Lingli, Wu Lijuan, Lee Grace, Xie Yangyiran, Hui Qiaoyan, Guerra James, Mertz Joseph, Nassar Khaled
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
Bayer AG, Wuppertal, Germany.
Diabetes. 2025 Jul 1;74(7):1220-1232. doi: 10.2337/db24-0739.
Oxidative stress has a major pathogenic role in diabetic retinopathy (DR), and neuroretina dysfunction is recognized as an early and important problem. Soluble guanylate cyclase (sGC) has been implicated for its neuroprotective effects in the central nervous system, but its role in the retina remains unclear. Here, we demonstrated in healthy human and rodent retinas the expression of sGC subunits GUCY1A1 and GUCY1B1 in vascular cells and neuronal elements, including retinal ganglion, bipolar, and amacrine cells. We provided evidence using in vitro and in vivo studies that sGC function is impaired by oxidative stress-induced damage in the retina. The sGC activator runcaciguat activated sGC in multiple retinal cell types and counteracted the inhibitory effect of damage induced by oxidative stress on the retina and retinal cells. In the rat retinal ischemia-reperfusion model, runcaciguat treatment improved neuroretinal and visual function as measured by electroretinography and optokinetic tracking and resulted in retinal morphologic improvement. In the streptozotocin-induced diabetic rat model, runcaciguat significantly improved neuroretinal function and improved inner plexiform layer thickness. These studies suggest that sGC signaling is involved in neuroretinal function and vision and that diabetes negatively affects this pathway, supporting restoring sGC activation as a novel therapy for early DR.
Soluble guanylate cyclase (sGC) subunits are expressed in retinal vascular and neuronal cells. Runcaciguat activates sGC impaired by oxidative stress in vitro and in vivo. Runcaciguat improves retinal neuronal function and morphology in rat models of ischemia-reperfusion and streptozotocin-induced diabetes. Restoring sGC activity is a novel therapeutic target for early diabetic retinopathy.
氧化应激在糖尿病视网膜病变（DR）中起主要致病作用，神经视网膜功能障碍被认为是一个早期且重要的问题。可溶性鸟苷酸环化酶（sGC）因其在中枢神经系统中的神经保护作用而受到关注，但其在视网膜中的作用仍不清楚。在此，我们在健康人类和啮齿动物视网膜中证实了sGC亚基GUCY1A1和GUCY1B1在血管细胞和神经元成分中的表达，包括视网膜神经节细胞、双极细胞和无长突细胞。我们通过体外和体内研究提供证据表明，视网膜中的氧化应激诱导损伤会损害sGC功能。sGC激活剂瑞卡西呱可在多种视网膜细胞类型中激活sGC，并抵消氧化应激诱导的损伤对视网膜和视网膜细胞的抑制作用。在大鼠视网膜缺血再灌注模型中，瑞卡西呱治疗可改善通过视网膜电图和视动跟踪测量的神经视网膜和视觉功能，并导致视网膜形态学改善。在链脲佐菌素诱导的糖尿病大鼠模型中，瑞卡西呱显著改善神经视网膜功能并增加内网状层厚度。这些研究表明，sGC信号传导参与神经视网膜功能和视觉，糖尿病会对该途径产生负面影响，支持恢复sGC激活作为早期DR的一种新疗法。
可溶性鸟苷酸环化酶（sGC）亚基在视网膜血管和神经细胞中表达。瑞卡西呱在体外和体内激活受氧化应激损害的sGC。瑞卡西呱可改善缺血再灌注和链脲佐菌素诱导的糖尿病大鼠模型中的视网膜神经元功能和形态。恢复sGC活性是早期糖尿病视网膜病变的一个新治疗靶点。
