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

Kihira,Yoshitaka; Fujimura,Yoshino; Tomita,Shuhei; Sato,Eiji

doi:10.3892/mmr.2023.13103

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
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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
Published online on: September 26, 2023 https://doi.org/10.3892/mmr.2023.13103
Article Number: 216

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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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1	Anelli T and Sitia R: Protein quality control in the early secretory pathway. EMBO J. 27:315–27. 2008. View Article : Google Scholar : PubMed/NCBI
2	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–90. 2011. View Article : Google Scholar : PubMed/NCBI
3	Walter P and Ron D: The unfolded protein response: From stress pathway to homeostatic regulation. Science. 334:1081–1086. 2011. View Article : Google Scholar : PubMed/NCBI
4	Schröder M and Kaufman RJ: The mammalian unfolded protein response. Annu Rev Biochem. 74:739–789. 2005. View Article : Google Scholar : PubMed/NCBI
5	Oyadomari S, Araki E and Mori M: Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis. 7:335–345. 2002. View Article : Google Scholar : PubMed/NCBI
6	Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, et al: Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: Possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation. 110:705–712. 2004. View Article : Google Scholar : PubMed/NCBI
7	Szegezdi E, Duffy A, O'Mahoney ME, Logue SE, Mylotte LA, O'brien T and Samali A: ER stress contributes to ischemia-induced cardiomyocyte apoptosis. Biochem Biophys Res Commun. 349:1406–1411. 2006. View Article : Google Scholar : PubMed/NCBI
8	Fawcett TW, Martindale JL, Guyton KZ, Hai T and Holbrook NJ: Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J. 339:135–141. 1999. View Article : Google Scholar : PubMed/NCBI
9	Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS and Lusis AJ: CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol. 182:466–476. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kumar A, Tikoo S, Maity S, Sengupta S, Sengupta S, Kaur A and Bachhawat AK: Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione. EMBO Rep. 13:1095–1101. 2012. View Article : Google Scholar : PubMed/NCBI
11	Crawford RR, Prescott ET, Sylvester CF, Higdon AN, Shan J, Kilberg MS and Mungrue IN: Human CHAC1 protein degrades glutathione, and mRNA induction is regulated by the transcription factors ATF4 and ATF3 and a bipartite ATF/CRE regulatory element. J Biol Chem. 290:15878–15891. 2015. View Article : Google Scholar : PubMed/NCBI
12	Chen MS, Wang SF, Hsu CY, Yin PH, Yeh TS, Lee HC and Tseng LM: CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway. Oncotarget. 8:114588–114602. 2017. View Article : Google Scholar : PubMed/NCBI
13	Oh-Hashi K, Nomura Y, Shimada K, Koga H, Hirata Y and Kiuchi K: Transcriptional and post-translational regulation of mouse cation transport regulator homolog 1. Mol Cell Biochem. 380:97–106. 2013. View Article : Google Scholar : PubMed/NCBI
14	Younis NS and Ghanim AMH: The protective role of celastrol in renal ischemia-reperfusion injury by activating Nrf2/HO-1, PI3K/AKT signaling pathways, modulating NF-κb signaling pathways, and inhibiting ERK phosphorylation. Cell Biochem Biophys. 80:191–202. 2022. View Article : Google Scholar : PubMed/NCBI
15	Hoppins S and Nunnari J: Mitochondrial dynamics and apoptosis-the ER connection. Science. 337:1052–1054. 2012. View Article : Google Scholar : PubMed/NCBI
16	Martin E, Lee YC and Murad F: YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components. Proc Natl Acad Sci USA. 98:12938–12942. 2001. View Article : Google Scholar : PubMed/NCBI
17	Vlahos CJ, Matter WF, Hui KY and Brown RF: A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 269:5241–5248. 1994. View Article : Google Scholar : PubMed/NCBI
18	García-Martínez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM and Alessi DR: Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J. 421:29–42. 2009. View Article : Google Scholar : PubMed/NCBI
19	Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR and Lee JC: SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364:229–233. 1995. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Surani MA: Glycoprotein synthesis and inhibition of glycosylation by tunicamycin in preimplantation mouse embryos: Compaction and trophoblast adhesion. Cell. 18:217–227. 1979. View Article : Google Scholar : PubMed/NCBI
22	Yoo J, Mashalidis EH, Kuk ACY, Yamamoto K, Kaeser B, Ichikawa S and Lee SY: GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat Struct Mol Biol. 25:217–224. 2018. View Article : Google Scholar : PubMed/NCBI
23	Hakulinen JK, Hering J, Brändén G, Chen H, Snijder A, Ek M and Johansson P: MraY-antibiotic complex reveals details of tunicamycin mode of action. Nat Chem Biol. 13:265–267. 2017. View Article : Google Scholar : PubMed/NCBI
24	Liu F, Ni W, Zhang J, Wang G, Li F and Ren W: Administration of curcumin protects kidney tubules against renal ischemia-reperfusion injury (RIRI) by modulating nitric oxide (NO) signaling pathway. Cell Physiol Biochem. 44:401–411. 2017. View Article : Google Scholar : PubMed/NCBI
25	Walker LM, Walker PD, Imam SZ, Ali SF and Mayeux PR: Evidence for peroxynitrite formation in renal ischemia-reperfusion injury: Studies with the inducible nitric oxide synthase inhibitor L-N(6)-(1-Iminoethyl)lysine. J Pharmacol Exp Ther. 295:417–422. 2000.PubMed/NCBI
26	Chatterjee PK, Patel NS, Sivarajah A, Kvale EO, Dugo L, Cuzzocrea S, Brown PA, Stewart KN, Mota-Filipe H, Britti D, et al: GW274150, a potent and highly selective inhibitor of iNOS, reduces experimental renal ischemia/reperfusion injury. Kidney Int. 63:853–865. 2003. View Article : Google Scholar : PubMed/NCBI
27	Luo J, Xia Y, Luo J, Li J, Zhang C, Zhang H, Ma T, Yang L and Kong L: GRP78 inhibition enhances ATF4-induced cell death by the deubiquitination and stabilization of CHOP in human osteosarcoma. Cancer Lett. 410:112–123. 2017. View Article : Google Scholar : PubMed/NCBI
28	Nomura Y, Sylvester CF, Nguyen LO, Kandeel M, Hirata Y, Mungrue IN and Oh-Hashi K: Characterization of the 5′-flanking region of the human and mouse CHAC1 genes. Biochem Biophys Rep. 24:1008342020.PubMed/NCBI
29	Schiffl H, Lang SM and Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med. 346:305–310. 2002. View Article : Google Scholar : PubMed/NCBI
30	Edelstein CL, Ling H and Schrier RW: The nature of renal cell injury. Kidney Int. 51:1341–1351. 1997. View Article : Google Scholar : PubMed/NCBI
31	DuBose TD Jr, Warnock DG, Mehta RL, Bonventre JV, Hammerman MR, Molitoris BA, Paller MS, Siegel NJ, Scherbenske J and Striker GE: Acute renal failure in the 21st century: Recommendations for management and outcomes assessment. Am J Kidney Dis. 29:793–799. 1997. View Article : Google Scholar : PubMed/NCBI
32	Basile DP: The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function. Kidney Int. 72:151–156. 2007. View Article : Google Scholar : PubMed/NCBI
33	Bonventre JV and Yang L: Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest. 121:4210–4221. 2011. View Article : Google Scholar : PubMed/NCBI
34	Kloner RA, Przyklenk K and Whittaker P: Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues. Circulation. 80:1115–1127. 1989. View Article : Google Scholar : PubMed/NCBI
35	Cao JY and Dixon SJ: Mechanisms of ferroptosis. Cell Mol Life Sci. 73:2195–209. 2016. View Article : Google Scholar : PubMed/NCBI
36	Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, Prokai A, Zuchtriegel G, Krombach F, Welz PS, et al: Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA. 111:16836–16841. 2014. View Article : Google Scholar : PubMed/NCBI
37	Li X, Ma N, Xu J, Zhang Y, Yang P, Su X, Xing Y, An N, Yang F, Zhang G, et al: Targeting ferroptosis: pathological mechanism and treatment of ischemia-reperfusion injury. Oxid Med Cell Longev. 2021:15879222021. View Article : Google Scholar : PubMed/NCBI