Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

Abstract

Aims/hypothesis We aimed to evaluate the effect of the mutant Wld S (slow Wallerian degeneration; also known as Wld) gene in experimental diabetes on early experimental peripheral diabetic neuropathy and diabetic retinopathy.Methods The experiments were performed in four groups of mice: wild-type (WT), streptozotocin (STZ)-induced diabetic WT, C57BL/Wld S and STZ-induced diabetic C57BL/Wld S . In each group, intraperitoneal glucose and insulin tolerance tests were performed; blood glucose, glycated haemoglobin and serum insulin were monitored. These mice were also subjected to the following behavioural tests: grasping test, hot-plate test and von Frey aesthesiometer test. For some animals, sciatic-tibial motor nerve conduction velocity, tail sensory nerve conduction velocity and eye pattern electroretinogram were measured. At the end of the experiments, islets were isolated to detect glucose-stimulated insulin secretion, ATP content and extent of apoptosis. The NAD/NADH ratio in islets and retinas was evaluated. Surviving retinal ganglion cells were estimated by immunohistochemistry. Results We found that the Wld S gene is expressed in islets and protects beta cells against multiple low doses of STZ by increasing the NAD/NADH ratio, maintaining the ATP concentration, and reducing apoptosis. Consistently, significantly higher insulin concentrations, lower blood glucose concentrations, and better glucose tolerance were observed in Wld S mice compared with WT mice after STZ treatment. Furthermore, Wld S alleviated abnormal sensory responses, nerve conduction, retina dysfunction and reduction of surviving retinal ganglion cells in STZinduced diabetic models. Conclusions/interpretation We provide the first evidence that expression of the Wld S gene decreases beta cell destruction and preserves islet function in STZ-induced diabetes, thus revealing a novel protective strategy for diabetic models.

A cross talk between class a scavenger receptor and receptor for advanced glycation end-products contributes to diabetic retinopathy

“…Previous investigations conducted in our laboratory have placed SR-A in the center of this process (46,48,50). Our new data suggest that SR-A suppresses RAGE-induced M1 polarization by inhibiting MKK7-dependent JNK activation.…”

“…Recent investigations by our laboratory and others have made a strong case for SR-A-mediated macrophage polarization in the pathogenesis of myocardial infarction (20), stroke (46), lung carcinogenesis (5), insulin resistance (51), and diabetic nephropathy (50). Of note, SR-A deletion exerts distinct effects on stress-induced organ injuries.…”

“…Mice were bred and maintained under specific pathogen free level conditions with a 12:12-h light-dark cycle and were fed regular chow diet and water. Diabetic mice were generated by a single intraperitoneal injection of streptozotocin (150 mg/kg in citrate buffer, 100 mmol/l, pH 4.5; Sigma) as previously described (50). Nondiabetic control mice were injected with an equal volume of vehicle.…”

“…Eyes were immediately placed in Davidson's fixative (11% glacial acetic acid, 2% neutral buffered formalin, and 32% ethanol in H2O) for 24 h, transferred to 70% ethanol for 24 h, and stored in PBS at 4°C. Eyes were embedded in paraffin, sectioned to 4 m, and stained with hematoxylin and eosin (H&E) as described in detail previously (50).…”

WldSameliorates renal injury in a type 1 diabetic mouse model

“…It attenuates the axon degeneration that is associated with several neurodegenerative disease models (13,18,19,36,38). In our previous study, we have shown that Wld S could attenuate experimental diabetes and early experimental peripheral diabetic neuropathy and diabetic retinopathy (52). Here, we wanted to determine whether the Wld S gene plays a renoprotective role during the progression of diabetic renal injury.…”