Nitric oxide prevents axonal degeneration by inducing HIF-1-dependent expression of erythropoietin

Sanjay C. Keswani, Marta Bosch-Marcé, Nicole Reed, Angela Fischer, Gregg L. Semenza, Ahmet Höke

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO) is a signaling molecule that can trigger adaptive (physiological) or maladaptive (pathological) responses to stress stimuli in a context-dependent manner. We have previously reported that NO may signal axonal injury to neighboring glial cells. In this study, we show that mice deficient in neuronal nitric oxide synthase (nNOS-/-) are more vulnerable than WT mice to toxin-induced peripheral neuropathy. The administration of NO donors to primary dorsal root ganglion cultures prevents axonal degeneration induced by acrylamide in a dose-dependent manner. We demonstrate that NO-induced axonal protection is dependent on hypoxia-inducible factor (HIF)-1-mediated transcription of erythropoietin (EPO) within glial (Schwann) cells present in the cultures. Transduction of Schwann cells with adenovirus AdCA5 encoding a constitutively active form of HIF-1α results in amelioration of acrylamide-induced axonal degeneration in an EPO-dependent manner. Mice that are partially deficient in HIF-1α (HIF-1α+/-) are also more susceptible than WT littermates to toxic neuropathy. Our results indicate that NO→HIF-1→EPO signaling represents an adaptive mechanism that protects against axonal degeneration.

Original languageEnglish (US)
Pages (from-to)4986-4990
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number12
DOIs
StatePublished - Mar 22 2011

ASJC Scopus subject areas

  • General

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