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

TL;DR

This study demonstrates that HIF1a in peripheral sensory neurons protects against diabetic nerve damage by reducing reactive oxygen species, suggesting a potential therapeutic target for diabetic peripheral neuropathy.

Contribution

It reveals a novel protective role of HIF1a in sensory neurons against diabetic neuropathy by modulating ROS levels, based on longitudinal analysis in a mouse model.

Findings

HIF1a deficiency accelerates nerve damage in diabetic mice.

HIF1a reduces ROS accumulation in sensory neurons.

HIF1a stabilization may prevent sensory loss in diabetes.

Abstract

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic complications. Mechanisms underlying nerve damage and sensory loss following metabolic dysfunction remain large unclear. Recently, hyperglycemia-induced mitochondrial dysfunction and the generation of ROS have gained attention as possible mechanisms of organ damage in diabetes. Hypoxia-inducible factor 1(HIF1a) is a key transcription factor activated by hypoxia, hyperglycemia, nitric oxide as well as ROS, suggesting a fundamental role in DPN susceptibility. Genetically-modified mutant mice, which conditionally lack HIF1a in peripheral sensory neurons (SNS-HIF1a-/-), 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 and measurements of reactive oxygen species (ROS) in sensory neurons in vivo were undertaken over several months post-STZ injections to delineate the role of HIF1a in DPN. Longitudinal behavioral and morphological analyses at 5, 13 and 24 wks post-STZ treatment revealed that SNS-HIF1a-/- developed stronger hyperglycemia-evoked losses of peripheral nociceptive sensory axons associated with stronger losses of mechano- and heat sensation with a faster onset than HIF1afl/fl mice. Mechanistically, these histomorphologic and behavioral differences were associated with significantly higher level of STZ-induced production of ROS in sensory neurons of SNS-HIF1a-/- mice as compared with HIF1afl/fl. Our results indicate that HIF1a 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. HIF1a stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes.