2. Academic Validation
  3. Activation of transcription factor HIF inhibits IL-1β-induced NO production in primary cultured rat hepatocytes

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

Affiliations

  • 1 Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: yoshiter@hirakata.kmu.ac.jp.
  • 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: okumura@hirakata.kmu.ac.jp.
  • 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: ysmatsuo-kyt@umin.ac.jp.
  • 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: okuyamat@hirakata.kmu.ac.jp.
  • 5 Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: t.michiura@izuo-saiseikai.gr.jp.
  • 6 Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: kaibori@hirakata.kmu.ac.jp.
  • 7 Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: umezakin@hirakata.kmu.ac.jp.
  • 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: bonohu@hiroshima-u.ac.jp.
  • 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: khirota-kyt@umin.ac.jp.
  • 10 Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. Electronic address: sekimotm@hirakata.kmu.ac.jp.
PMID: 35460897 DOI: 10.1016/j.niox.2022.04.002
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.

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