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

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 EPOdependent 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.

Epo and Non-hematopoietic Cells: What Do We Know?

“…However when treated with a neuronal nitric oxide synthase (nNOS) inhibitor the neurons lost their ability to induce EpoR expression in hypoxia and thus were not protected (104). In line with this finding another study demonstrated that nNOS knockout mice are more susceptible to peripheral neuropathy than their wild type counterparts due to the absence of NO-mediated activation of HIF-1 and subsequent downstream neuroprotection by Epo (105). Ex vivo experiments showed that protection recovered by using low doses of NOS donors was almost completely abrogated by Epo siRNA.…”

Herpesvirus entry mediator regulates hypoxia-inducible factor–1α and erythropoiesis in mice

“…There is compelling evidence that HIF-1α can be upregulated by various stimuli other than hypoxia (12)(13)(14)(15)(16)(17)(18). In addition, recent studies directly revealed that HIF-1α contributes to NO-mediated Epo production in normoxic condition (35). Nevertheless, we cannot fully exclude the possibility that weak expression of HIF-2α, which was below the detection limit in our immunoblotting methods, may also contribute to Epo upregulation in our model.…”

“…The stimulatory role of NO in Epo production was previously reported in models using pharmacological methods to increase NO production. For instance, inclusion of S-nitroso-N-acetyl-DL-penicillamine, an NO donor, to primary rat dorsal root ganglion cultures upregulates Epo transcription in glial cells in a HIF-1α-dependent fashion (35). In addition, daily injections of sodium nitroprusside, a generator of NO, significantly increased serum Epo levels (36).…”

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…The structurally related fungal sesquiterpenes pycnidione, epolone A, and epolone B induce erythropoietin expression via HIF-1a activation (Cai et al, 1998;Wanner et al, 2000). In a study of cultured dorsal root ganglia, it was found that neuronal NO induces the HIF-1-dependent expression of erythropoietin in adjacent Schwann cells, and the erythropoietin in turn protects axons of the neurons against neurotoxin-induced degeneration (Keswani et al, 2011). In contrast with the Nrf2 stress response pathway, far fewer studies have investigated the effects of phytochemicals on the HIF-1 pathway (Table 2).…”