Soluble guanylate cyclase in diabetic retinopathy

Diabetic retinopathy is a major cause of blindness worldwide. Current treatments are available only advanced stages of DR. There is a great need for identifying regulators and therapeutic targets. Research advances have expanded our understanding of DR. These include the role of protective factors in DR, the pathophysiologic effect of oxidative stress, and the multi-faceted nature of DR as a disease of the neurovascular unit that involves multiple cell types. This includes neuroretinal dysfunction and neurodegeneration that are early abnormities in DR which can contribute to disease progression. Soluble guanylate cyclase (sGC) is a key enzyme for nitric oxide (NO) signaling. Oxidative stress is known to inhibit sGC in systemic settings, including diabetes, via oxidation of the sGC prosthetic heme, leading to its inactivation and eventual loss. This is notable since oxidative stress is known to be an important driver of DR progression. Drugs promoting sGC are in use for some systemic conditions and are continuing to be actively developed, highlighting the translational potential of targeting this molecule. Our lab has found that an sGC activator drug exerts neuroprotective effects in rodent models of diabetic retinopathy. We have further found evidence for a functional role for sGC in the retina. In this proposal, we seek to expand our studies of sGC with respect to its role in diabetic retinopathy. We will use a combination of in vitro and in vivo approaches to explore the potential inactivation of sGC in retina by diabetes and its stressors. In addition, we will explore the cell-specific roles of sGC in the retina using conditional knockout mice. The proposal could advance sGC as an important regulator and target in DR and also increase understanding of the interplay of retinal cell types in this condition, shedding further light into DR as a disease of the neurovascular unit.