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Diabetic peripheral neuropathy (DPN) is one of the most common diabetic complications. Mechanisms underlying nerve damage and sensory loss following metabolic dysfunction remain largely unclear. Recently, hyperglycemia-induced mitochondrial dysfunction and the generation of reactive oxygen species (ROS) have gained attention as possible mechanisms of organ damage in diabetes. Hypoxia-inducible factor 1 (HIF1α) is a key transcription factor activated by hypoxia, hyperglycemia, nitric oxide as well as ROS, suggesting a fundamental role in DPN susceptibility. We analyzed regulation of HIF1α in response to prolonged hyperglycemia. Genetically modified mutant mice, which conditionally lack HIF1α in peripheral sensory neurons (SNS-HIF1α -/- ), were analyzed longitudinally up to 6 months in the streptozotocin (STZ) model of type1 diabetes. Behavioral measurements of sensitivity to thermal and mechanical stimuli, quantitative morphological analyses of intraepidermal nerve fiber density, measurements of ROS, ROS-induced cyclic GMP-dependent protein kinase 1α (PKG1α), and levels of vascular endothelial growth factor (VEGF) in sensory neurons in vivo were undertaken over several months post-STZ injections to delineate the role of HIF1α in DPN. Longitudinal behavioral and morphological analyses at 5, 13, and 24 weeks post-STZ treatment revealed that SNS-HIF1α -/- developed stronger hyperglycemia-evoked losses of peripheral nociceptive sensory axons associated with stronger losses of mechano- and heat sensation with a faster onset than HIF1α fl/fl mice. Mechanistically, these histomorphologic, behavioral, and biochemical differences were associated with a significantly higher level of STZ-induced production of ROS and ROS-induced PKG1α dimerization in sensory neurons of SNS-HIF1α -/- mice as compared with HIF1α fl/fl . We found that prolonged hyperglycemia induced VEGF expression in the sciatic nerve which is impaired in SNS-HIF1α mice. Our results indicate that HIF1α is as an upstream modulator of ROS in peripheral sensory neurons and exerts a protective function in suppressing hyperglycemia-induced nerve damage by limiting ROS levels and by inducing expression of VEGF which may promote peripheral nerve survival. Our data suggested that HIF1α stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes. KEY MESSAGES: • Impaired hypoxia-inducible factor 1α (HIF1α) signaling leads to early onset of STZ-induced loss of sensation in mice. • STZ-induced loss of sensation in HIF1α mutant mice is associated with loss of sensory nerve fiber in skin. • Activation of HIF1α signaling in diabetic mice protects the sensory neurons by limiting ROS formation generated due to mitochondrial dysfunction and by inducing VEGF expression.

journal of molecular medicine

Hypoxia-inducible factor 1α protects peripheral sensory neurons from diabetic peripheral neuropathy by suppressing accumulation of reactive oxygen species.