Wlds Protects Against Diabetic Retinopathy In An Experimental Model Of Diabetes In Mice

The Wlds mouse carries a dominant mutation that delays Wallerian degeneration in the distal stump of an injured axon. Wlds (also known as Wld) mutation comprises an85kb tandem triplication, which results in overproduction of slow Wallerian degeneration (Wlds) protein. This protein is composed of the N-terminal70amino acids of Ube4b ubiquitination assembly factor, fused to the complete sequence of nicotinamide mononucleotide adenylyltransferasel (NMNAT1), an enzyme in the NAD biosynthetic pathway that generates NAD.The polyol pathway is one of the possible biochemical mechanisms by which hyperglycemia could impair the function and structure of the cells affected by diabetic complications. As possible hypothesis for the pathogenesis of diabetic complications, the polyol theory, alterations in abnormal changes of the redox state (NAD/NADH ratio). Recently, increasing evidence suggests that glycation and oxidative stress may have a cross-link with polyol pathway, contributing to the development of diabetic complications. With the excessive DNA damage resulting from reactive oxygen species accumulation, poly(ADP-ribose) polymerase (PARP) is highly activated. Continuous PARP activity in the pancreas leads to depletion of its substrate, NAD, to non-physiological levels, energy failure, cell death. Whether Wlds can antagonise diabetic retinopathy is not yet known.The Wlds mouse has been shown to have protective properties in different types of neurodegenerative disease models with axonal degeneration. Here, we provide evidence that Wlds could attenuate early experimental diabetic retinopathy (DR). Aims/hypothesis To investigate the effect of the mutant Wlds (slow Wallerian degeneration; also known as Wld) gene in experimental diabetes on early experimental diabetic retinopathy.MethodsDiabetic animal model was produced by intraperitoneal injection of streptozotocin (STZ). The successful model was identified based on the blood glucose value>11.2mmol/L. Then the experiments were performed in four groups of mice wild-type (WT), streptozotocin (STZ)-induced diabetic WT, Wlds and STZ-induced diabetic Wlds. Each group contained6mice. In each group, eye pattern electroretinogram (pERG) were measured. At the end of the experiments, The NAD/NADH ratio in retinas was evaluated. The cell numbers of retinal ganglion cell layer and surviving retinal ganglion cells were estimated by HE stain and immunohistochemistry.ResultsThe diabetic model was successfully produced in mouse received injection of STZ. Wlds alleviated abnormal retina dysfunction and reduction of surviving retinal ganglion cells in STZ induced diabetic models by increasing the NAD/NADH ratio. Conclusions We provide the first evidence that expression of the Wlds gene protect early experimental diabetic retinopathy, thus revealing a novel protective strategy for diabetic models, indicating Wlds be a target for the treatment of retinal degeneration diseases and a new avenue to explore the mechanism of diabetic retinopathy.