Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice

Abstract

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 liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)–producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. 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 skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores 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 that targeting LXR/Nox4 axis is a promising therapeutic approach.

The macrophage: a key player in the pathophysiology of peripheral neuropathies

“…External and internal stressors, such as inflammation, disrupt the balance between pro and anti-oxidant systems leading to an oxidative burst [ 91 ]. ROS were found to be elevated in sciatic nerves of CMT1A rats [ 92 ] as well as in sciatic nerves after crush injury [ 93 ] and of diabetic mice [ 94 ]. Moreover, sciatic nerves exposed to stress by non-freezing cold presented high ROS production associated with reperfusion injury and pathological destruction [ 95 ].…”

NADPH Oxidases in Pain Processing

“…As changes in peripheral myelin may result in the sensitization of peripheral nerves and spontaneous action potentials, these alterations promoted by Nox4 might contribute to the manifestation of neuropathic pain [ 114 , 115 , 116 , 117 ]. In line with this, action potential firing in DRG neurons after peripheral nerve injury was reduced in the absence of Nox4 [ 27 ], and the inhibition of Nox4 by GKT137831 in a model of hyperglycemia-induced neurophysiological disorders restored expression of peripheral myelin proteins and prevented sensorimotor defects in mice, further suggesting a contribution of Nox4 in diabetes-induced peripheral neuropathy [ 118 ]. Another study revealed that the induction of proinflammatory cytokines such as TNFα and ROS production induced by peripheral nerve injury was less pronounced in Nox4 knockout mice [ 75 ].…”

Diabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future

“…In addition, ROS derived from NOX4 and NOX1 have been involved in DR. H 2 O 2 produced by NOX4 was demonstrated to induce blood–retina barrier breakdown by increasing VEGF expression [ 64 ], whereas superoxide originated from NOX1 has been involved in retinal cell damage and death [ 65 ]. In chronic diabetic neuropathy, ROS overproduction resulting from the crosstalk between liver X receptor and NOX4 was recently identified as a promising therapeutic approach to preserve Schwann cell integrity in diabetic mice [ 66 ]. In addition to genetic targeting, pharmacologic blockade of NOX4 and NOX1 showed promising results in preventing renal disease and atherosclerosis in preclinical models [ 41 , 61 ], but failed to reduce albuminuria in a short-term Phase II trial in patients with T2DM (ClinicalTrial.gov registration No.…”