Activation of transcription factor HIF inhibits IL-1β-induced NO production in primary cultured rat hepatocytes PMID: 35460897

ADC Targets in Oncology

2026-04-10

Activation of transcription factor HIF inhibits IL-1β-induced NO production in primary cultured rat hepatocytes

Nitric Oxide. 2022 Jul 1;124:1-14. doi: 10.1016/j.niox.2022.04.002.

Terufumi Yoshida ¹ , Tadayoshi Okumura ² , Yoshiyuki Matsuo ³ , Tetsuya Okuyama ⁴ , Taku Michiura ⁵ , Masaki Kaibori ⁶ , Nodoka Umezaki ⁷ , Hidemasa Bono ⁸ , Kiichi Hirota ⁹ , Mitsugu Sekimoto ¹⁰

Affiliations

1. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].
2. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan; Research Organization of Science and Technology, Ritsumeikan University, 1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan. Electronic address: [email protected].
3. Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].
4. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan; Research Organization of Science and Technology, Ritsumeikan University, 1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan. Electronic address: [email protected].
5. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].
6. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].
7. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].
8. Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, 3-10-23 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-0046, Japan. Electronic address: [email protected].
9. Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].
10. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: [email protected].

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-1β-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-1β. Moreover, roxadustat suppressed IL-1β-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-1β-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.

Keywords

Hepatocyte; Hypoxia; Hypoxia-inducible factor; IL-1β; NO; iNOS.