Diabetic retinopathy (DR) is a major complication of diabetes and it is a leading cause of legal blindness in working age adults in the developed world. For many years DR has been defined as a vascular pathology characterized by increased vascular permeability, which leads to edema and endothelial and pericyte cell death. This vascular based definition has expanded given the many recent reports describing early electrophysiological pathology and neuronal/glial degenerative changes that precede the vascular changes in both humans and animals. In lab animals, these retinal changes produce significant reductions in both visual acuity and contrast sensitivity after only one month of hyperglycemia. In diabetic patients with no clinically detectable DR, they still show impairment of their ERG pattern responses, b-wave scotopic bright flash ERGs, a- and b-wave photopic single flash ERGs, and their oscillatory potential responses. Optical coherence tomography reveals significant thinning in the ganglion cell layer, ganglion cell fiber layer, and inner nuclear layer in diabetic patients with no or minimal vascular DR. These results indicate that both diabetic patients and animals have similar specific early neuronal defects that occur before the vascular pathology. However, the cause of the early neuronal pathology is not known.
Figure 1: ADM-signaling pathway.
(Click on figure for a larger image.)
Because this early neuronal pathology precedes the microvascular changes that are used to diagnose DR, early intervention is critical to reduce or prevent vision loss. Although many aspects of the biochemical basis for the vascular pathology are understood, there is not currently a clear understanding of the causes for the early neuronal pathology, nor are there clinical interventions.
In animal models, nitric oxide (NO) plays a critical role in the vascular pathology in DR, and inhibiting NO signaling reduces this pathology. There is also increased NO production that co-occurs with the early neuronal pathology, before the vascular pathology; but no one has examined a role for NO in these early neural deficits. We want to determine the causes of this increased NO and assess whether selectively inhibiting it reduces the early neuronal pathology.
Nitric oxide (NO) has normal physiological functions in every retinal cell type, and every retinal cell type can potentially make NO. NO is also involved in many ocular pathologies including diabetic retinopathy and inhibiting NO is often beneficial. NO signaling is regulated by many factors, both in normal retinal function and pathology, making it desirable to target just the pathological pathways. Our research focuses on how NO can be selectively targeted to decrease the neuronal and vascular pathology in diabetic retinopathy. We are testing the hypotheses that diabetes increases the retinal levels of adrenomedullin (ADM), which in turn activates neuronal nitric oxide synthase (nNOS) to increase retinal NO production to pathological levels. Our results are clarifying the role of specific NOS isoforms and ADM in diabetic retinopathy and how these pathways can be optimally targeted to treat the pathology. We have recently found that inhibiting the ADM/NO signaling pathway can indeed reduce the neuronal pathology in early DR. Upregulation of ADM is also found in proliferative vitreoretinopathy, uveitis, vitreoretinal disorders, primary open angle glaucoma, and retinitis pigmentosa. A clearer understanding of the ADM/NOS/NO signaling pathways and how they can be manipulated in retina may have broad implications for much ocular pathology.