Neuroprotective Effect of a Novel Soluble Guanylate Cyclase Activator (sGCa) Runcaciguat in Diabetes and Ischemic Retinopathy

Abstract

Oxidative stress has a major pathogenic role in diabetic retinopathy, 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 expression of sGC subunits GUCY1A1 and GUCY1B1 in healthy human and rodent retina in vascular cells and neuronal elements including retinal ganglion cells, 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 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 STZ-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.