Activation of 20-HETE Synthase Triggers Oxidative Injury and Peripheral Nerve Damage in Type 2 Diabetic Mice
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Elsevier B.V.
Abstract
Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. Perspective: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus. © 2022 The Authors
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20-hete, Ampk, Diabetic peripheral neuropathy, Insulin resistance, Oxidative stress, Amp-activated protein kinases, Animals, Cytochrome p-450 cyp4a, Diabetes mellitus, experimental, Diabetes mellitus, type 2, Diabetic neuropathies, Hydroxyeicosatetraenoic acids, Metformin, Mice, Nad, Peripheral nerve injuries, Peripheral nerves, Reactive oxygen species, 20 hydroxyicosatetraenoic acid, 20 hydroxyicosatetraenoic acid synthetase, Agents acting on the peripheral nervous and neuromuscular systems, Antioxidant, Beclin 1, Cytochrome p450 4a, Cytochrome p450 inhibitor, Hemoglobin a1c, Het 0016, Hydroxymethylglutaryl coenzyme a reductase kinase, Insulin, Lc3b protein, Myelin protein, Myelin protein zero, Neuroprotective agent, Peptides and proteins, Peripheral myelin protein 22, Protein, Reactive oxygen metabolite, Synthetase, Unclassified drug, 20-hydroxy-5,8,11,14-eicosatetraenoic acid, Hydroxyicosatetraenoic acid, Nicotinamide adenine dinucleotide, Ampk signaling, Animal experiment, Animal model, Animal tissue, Antioxidant activity, Article, Autophagy (cellular), Controlled study, Diabetic neuropathy, Drug efficacy, Drug mechanism, Enzyme activation, Enzyme inactivation, Enzyme inhibition, Glycemic index, Hyperglycemia, Male, Motor nerve conduction, Mouse, Myelin sheath, Neuropathology, Neuroprotection, Non insulin dependent diabetes mellitus, Nonhuman, Outcome assessment, Peripheral nerve, Peripheral nerve injury, Protein expression level, Sensorimotor neuropathy, Sensory nerve conduction velocity, Signal transduction, Animal, Complication, Experimental diabetes mellitus, Metabolism