Neuroprotective Effect of a Novel Soluble Guanylate Cyclase Activator Runcaciguat in Diabetic and Ischemic Retinopathy

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. ARTICLE HIGHLIGHTS: 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.