  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.
