Targeting the NADPH Oxidase-4 and Liver X Receptor Signaling Axis Preserve Schwann Cell Integrity in Diabetic Mice.

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as Diabetic Peripheral Neuropathy (DPN). This work highlights the role of the oxysterol/LXR signaling pathway and the crosstalk with the reactive oxygen species (ROS) producing enzyme, NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Herein, we assess behavioral, molecular and physio-pathological changes in cultured Schwann cells as well as in the sciatic nerve of a type 1 diabetic (T1DM) murine model, and skin biopsies from type 2 diabetic (T2DM) patients. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by a defective peripheral myelin genes expression in MPZ and PMP22. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in T2DM patients. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro was shown to attenuate diabetes-induced ROS production, SC and peripheral nerve dysfunction and preserve the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest the targeting of the LXR/Nox4 axis as a promising therapeutic approach.