Inhibition of serine racemase prevents retinopathy in diabetic mice

A single-nucleotide polymorphism in the serine racemase (SRR)-encoding gene, Srr, is associated with an increased risk of type 2 diabetes. Studies, including our own, demonstrate that SRR is linked to a complication of diabetes, diabetic retinopathy (DR), and deletion of Srr protects diabetic animals from developing retinopathy. We investigate the feasibility and mechanisms of SRR inhibition as a strategy to prevent DR. SRR proteins in the retinas of db/db mice were approximately 50 % higher than C57BLKS/J wild-type (WT) mice, while D-serine levels in the aqueous humor were more than two-fold higher. Oral gavage of l-aspartic acid β-hydroxamate (L-ABH) improved b-wave amplitudes in electroretinogram recordings under both photopic and scotopic conditions. It also protected the inner retina in db/db mice by reducing the loss of retinal ganglion cells, endothelial cells, and pericytes, as well as decreasing the activation of Müller cells. In high glucose and hypoxia, interleukin-1 and interleukin-18 mRNA levels were lower in Srr-deleted Müller cell cultures than in WT cultures. Intravitreal injection of L-ABH mitigated glutamate-induced neurotoxicity in the retina. Systemically, L-ABH maintained euglycemia and improved glucose tolerance in db/db mice by inhibiting liver gluconeogenesis through restricting the expansion of pancreatic islet α-cells. Altogether, our results demonstrate that SRR inhibition prevents retinopathy in diabetic animals by blocking excitotoxicity and Müller cell-mediated inflammation in the retina, while also maintaining glucose homeostasis. This is the first demonstration that pharmacological blockade of SRR improves retinopathy and normalizes glucose levels in a type 2 diabetes model.