Activation of transcription factor HIF inhibits IL-1ß-induced NO production in primary cultured rat hepatocytes.
Nitric Oxide
; 124: 1-14, 2022 07 01.
Article
en En
| MEDLINE
| ID: mdl-35460897
ABSTRACT
Roxadustat and other hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have recently been approved for the treatment of chronic renal anemia. In macrophages and monocytes, the activation of HIF-1 by pro-inflammatory cytokines induces iNOS expression and activity through the NF-κB pathway to produce nitric oxide (NO), which causes liver injury when excessively produced. Few studies have reported a relationship between HIF activity and iNOS induction in hepatocytes. We investigated the effect of drug- and hypoxia-induced HIF activations on NO production in primary cultured rat hepatocytes. Roxadustat treatment and hypoxic conditions activated HIF. Contrary to expectations, HIF-PHI treatment and hypoxia inhibited IL-1ß-induced NO production. RNA-Seq analysis of mRNA expression in rat hepatocytes showed that roxadustat treatment decreased the expression of genes related to inflammation, and genes in the NF-κB signaling pathway were induced by IL-1ß. Moreover, roxadustat suppressed IL-1ß-activated signaling pathways in an HIF-dependent manner. GalN/LPS-treated rats were used as in vivo models of hepatic injury, and roxadustat treatment showed a tendency to suppress the death of rats. Therefore, exogenous HIF-1 activation, including HIF-PHI and hypoxia exposures, suppressed IL-1ß-induced iNOS mRNA expression and subsequent NO production in hepatocytes, by suppressing the NF-κB signaling pathway. Roxadustat treatment suppresses the expression of pro-inflammatory genes by activating HIF, and thus may exhibit hepatoprotective effects.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
FN-kappa B
/
Hepatocitos
/
Factor 1 Inducible por Hipoxia
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Interleucina-1beta
/
Óxido Nítrico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Nitric Oxide
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2022
Tipo del documento:
Article