| First Author | Rojas DR | Year | 2018 |
| Journal | J Mol Med (Berl) | Volume | 96 |
| Issue | 12 | Pages | 1395-1405 |
| PubMed ID | 30361814 | Mgi Jnum | J:295518 |
| Mgi Id | MGI:6453911 | Doi | 10.1007/s00109-018-1707-9 |
| Citation | Rojas DR, et al. (2018) Hypoxia-inducible factor 1alpha protects peripheral sensory neurons from diabetic peripheral neuropathy by suppressing accumulation of reactive oxygen species. J Mol Med (Berl) 96(12):1395-1405 |
| abstractText | 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 (HIF1alpha) 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 HIF1alpha in response to prolonged hyperglycemia. Genetically modified mutant mice, which conditionally lack HIF1alpha in peripheral sensory neurons (SNS-HIF1alpha(-/-)), 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 1alpha (PKG1alpha), 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 HIF1alpha in DPN. Longitudinal behavioral and morphological analyses at 5, 13, and 24 weeks post-STZ treatment revealed that SNS-HIF1alpha(-/-) developed stronger hyperglycemia-evoked losses of peripheral nociceptive sensory axons associated with stronger losses of mechano- and heat sensation with a faster onset than HIF1alpha(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 PKG1alpha dimerization in sensory neurons of SNS-HIF1alpha(-/-) mice as compared with HIF1alpha(fl/fl). We found that prolonged hyperglycemia induced VEGF expression in the sciatic nerve which is impaired in SNS-HIF1alpha mice. Our results indicate that HIF1alpha 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 HIF1alpha stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes. KEY MESSAGES: * Impaired hypoxia-inducible factor 1alpha (HIF1alpha) signaling leads to early onset of STZ-induced loss of sensation in mice. * STZ-induced loss of sensation in HIF1alpha mutant mice is associated with loss of sensory nerve fiber in skin. * Activation of HIF1alpha signaling in diabetic mice protects the sensory neurons by limiting ROS formation generated due to mitochondrial dysfunction and by inducing VEGF expression. |
