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Article

Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole

  • Authors:
    • Yoshitaka Kihira
    • Yoshino Fujimura
    • Shuhei Tomita
    • Eiji Sato
  • View Affiliations / Copyright

    Affiliations: Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729‑0292, Japan, Department of Pharmacology, Osaka Metropolitan University Graduate School of Medicine, Osaka 558‑8585, Japan
  • Article Number: 216
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    Published online on: September 26, 2023
       https://doi.org/10.3892/mmr.2023.13103
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Abstract

Glutathione‑specific γ‑glutamylcyclotransferase 1 (CHAC1), is an unfolded protein response‑induced gene. Although it has been previously reported that CHAC1 transcription is regulated by activating transcription factor (ATF) 4, ATF3 and CCAAT/enhancer‑binding protein β (C/EBPβ), the signaling pathways that regulate CHAC1 are largely unknown. It was revealed that 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole (YC‑1; PubChem ID: 5712), a nitric oxide‑independent activator of soluble guanylyl cyclase (sGC), increases CHAC1 levels in cultured human kidney proximal tubular cells (HK‑2). Therefore, in the present study, the signaling pathways that induce CHAC1 by YC‑1 were investigated in HK‑2 cells. YC‑1 induced CHAC1 expression in a dose‑ and time‑dependent manner. KT5823, an inhibitor of cGMP‑dependent protein kinase (PKG), partially inhibited CHAC1 upregulation, indicating that the sGC‑cGMP‑PKG pathway participates in CHAC1 regulation. These results also suggested that other signaling pathways are involved in the regulation of CHAC1. Since antibody array analysis showed the activation of p38, mTOR and Akt, the involvement of these factors was further investigated. Although LY294002 and KU0063794 (inhibitors of Akt and mTOR, respectively) inhibited YC‑1‑induced CHAC1 expression, SB203580 (an inhibitor of p38) did not. These results indicated that CHAC1 is regulated by the Akt‑mTOR pathway. In addition, YC‑1 induced endoplasmic reticulum (ER) stress, a regulator of CHAC1 induction. These findings suggested that CHAC1 is regulated by YC‑1 through the sGC‑cGMP‑PKG, Akt‑mTOR and ER stress pathways. The present study demonstrated that CHAC1 induction reduced the intracellular glutathione concentration, indicating that CHAC1 plays an important role in intracellular redox homeostasis in tubular cells.
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Copy and paste a formatted citation
Spandidos Publications style
Kihira Y, Fujimura Y, Tomita S and Sato E: Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole. Mol Med Rep 28: 216, 2023.
APA
Kihira, Y., Fujimura, Y., Tomita, S., & Sato, E. (2023). Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole. Molecular Medicine Reports, 28, 216. https://doi.org/10.3892/mmr.2023.13103
MLA
Kihira, Y., Fujimura, Y., Tomita, S., Sato, E."Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole". Molecular Medicine Reports 28.5 (2023): 216.
Chicago
Kihira, Y., Fujimura, Y., Tomita, S., Sato, E."Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole". Molecular Medicine Reports 28, no. 5 (2023): 216. https://doi.org/10.3892/mmr.2023.13103
Copy and paste a formatted citation
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Spandidos Publications style
Kihira Y, Fujimura Y, Tomita S and Sato E: Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole. Mol Med Rep 28: 216, 2023.
APA
Kihira, Y., Fujimura, Y., Tomita, S., & Sato, E. (2023). Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole. Molecular Medicine Reports, 28, 216. https://doi.org/10.3892/mmr.2023.13103
MLA
Kihira, Y., Fujimura, Y., Tomita, S., Sato, E."Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole". Molecular Medicine Reports 28.5 (2023): 216.
Chicago
Kihira, Y., Fujimura, Y., Tomita, S., Sato, E."Signaling pathways upregulating glutathione‑specific γ‑glutamylcyclotransferase 1 by 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole". Molecular Medicine Reports 28, no. 5 (2023): 216. https://doi.org/10.3892/mmr.2023.13103
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