CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress
Main Article Content
Keywords
acute kidney injury, apoptosis, CHAC1, ferroptosis, oxidative stress
Abstract
Background: Sepsis-induced acute kidney injury (AKI) is a singularly grievous and life-threatening syndrome. Its pathogenesis is closely related to inflammatory response, apoptosis, oxidative stress, and ferroptosis. Cation transport regulator-like protein 1 (CHAC1), as a proapoptic factor, may be involved in apoptosis, oxidative stress, and ferroptosis. This study aimed to explore the role of CHAC1 in the lipopolysaccharide (LPS)-induced the human renal proximal tubular epithelial (HK-2) cells.
Methods: HK-2 cells were challenged with LPS to construct a model of sepsis-induced AKI in vitro. The role of CHAC1 in the LPS-induced HK-2 cells was explored using Western blot assay, cell counting kit-8 (CCK-8), flow cytometry, and colorimetric assays. Additionally, N-acetyl cysteine (NAC) was incubated with HK-2 cells to define deeply the relation between oxidative stress and apoptosis or ferroptosis.
Results: The expression of CHAC1 was enhanced in the kidney tissues of mice with sepsis--induced multiple organ dysfunction syndrome (MODS), through the Gene Expression Omnibus database (GSE60088 microarray dataset), and in the LPS-induced HK-2 cells. The cell viability was significantly reduced by LPS treatment, which was at least partly restored by the transfection of siCHAC1#1 and siCHAC1#2 but not siNC. In addition, down-regulation of CHAC1 counteracted the LPS-induced reactive oxygen species level and malonaldehyde concentrations while restored the LPS-induced glutathione concentrations. Meanwhile, interference of CHAC1 neutralized LPS-induced apoptosis rate, and the relative level of cleaved poly(ADP-ribose) polymerase (PARP)/PARP, and cleaved caspase-3/caspase-3. In addition, silencing of CHAC1 recovered the LPS-induced enhanced protein level of glutathione peroxidase 4 (GPx4) whereas antagonized the LPS-induced relative protein level of ACSL4 and that of iron. Moreover, application of NAC inverted the effect of CHAC1 on apoptosis and ferroptosis in HK-2 cells.
Conclusion: CHAC1 exacerbated ferroptosis and apoptosis by enhancing oxidative stress in LPS-induced HK-2 cells.
References
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23. Liu Y, Li M, Shi D, Zhu Y. Higher expression of cation transport regulator-like protein 1 (CHAC1) predicts of poor outcomes in uveal melanoma (UM) patients. Int Ophthalmol. 2019;39:2825–32. 10.1007/s10792-019-01129-1
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29. Jin Y, Sun L, Liu K-C. Effect of sufentanil on the viability and apoptosis of cervical cancer cells via the inactivation of PI3K/AKT/mTOR signaling pathway. Eur J Gynaecol Oncol. 2021;42:325–32. 10.31083/j.ejgo.2021.02.2257
30. Qian D, Zhu Y, Xu L, Dong T, Chen T, Yu Z. Icariin induces apoptosis in breast cancer MCF-7 cells by regulating the MELK-mediated PI3K/AKT signaling pathway. Eur J Gynaecol Oncol. 2021;42:957–65. 10.31083/j.ejgo4205144
31. Huang G, Bao J, Shao X, Zhou W, Wu B, Ni Z, et al. Inhibiting pannexin-1 alleviates sepsis-induced acute kidney injury via decreasing NLRP3 inflammasome activation and cell apoptosis. Life Sci. 2020;254:117791. 10.1016/j.lfs.2020.117791
32. Chen F, Wang W, Cai X, Yu H, Qu C, Zhang X, et al. Methyl jasmonate reduces the inflammation and apoptosis of HK-2 cells induced by LPS by regulating the NF-κB pathway. Signa Vitae. 2021;17:218–24.
33. Lu SJ, Xu JH, He ZF, Wu P, Ning C, Li HY. Innate immune molecule surfactant protein D attenuates sepsis-induced acute kidney injury through modulating apoptosis and NFκB-mediated inflammation. Int Wound J. 2020;17:100–06. 10.1111/iwj.13237
34. Nadeem A, Ahmad SF, Al-Harbi NO, Ibrahim KE, Alqahtani F, Alanazi WA, et al. Bruton’s tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice. Int Immunopharmacol. 2021;90:107123. 10.1016/j.intimp.2020.107123
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36. Liang NN, Zhao Y, Guo YY, Zhang ZH, Gao L, Yu DX, et al. Mitochondria-derived reactive oxygen species are involved in renal cell ferroptosis during lipopolysaccharide-induced acute kidney injury. Int Immunopharmacol. 2022;107:108687. 10.1016/j.intimp.2022.108687
37. Chen PH, Shen WL, Shih CM, Ho KH, Cheng CH, Lin CW, et al. The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology. 2017;116:300–14. 10.1016/j.neuropharm.2016.12.011
38. Duan X, Wen Z, Shen H, Shen M, Chen G. Intracerebral hemorrhage, oxidative stress, and antioxidant therapy. Oxid Med Cell Longev. 2016;2016:1203285. 10.1155/2016/1203285
39. Yu Y, Yan Y, Niu F, Wang Y, Chen X, Su G, et al. Ferroptosis: A cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov. 2021;7:193. 10.1038/s41420-021-00579-w
40. Cui Y, Li F, Zhu X, Xu J, Muhammad A, Chen Y, et al. Alfalfa saponins inhibit oxidative stress-induced cell apoptosis through the MAPK signaling pathway. Redox Rep. 2022;27:1–8. 10.1080/13510002.2021.2017681
41. Pang Z, Jiang Z, Zhu R, Song C, Tang H, Cao L, et al. Bardoxolone-methyl prevents oxidative stress-mediated apoptosis and extracellular matrix degradation in vitro and alleviates osteoarthritis in vivo. Drug Des Devel Ther. 2021;15:3735–47. 10.2147/DDDT.S314767
42. Lu S, Song Y, Luo R, Li S, Li G, Wang K, et al. Ferroportin-dependent iron homeostasis protects against oxidative stress-induced nucleus pulposus cell ferroptosis and ameliorates intervertebral disc degeneration in vivo. Oxid Med Cell Longev. 2021;2021:6670497. 10.1155/2021/6670497
2. Liang W, Guo L, Liu T, Qin S. MEF2C alleviates acute lung injury in cecal ligation and puncture (CLP)-induced sepsis rats by up-regulating AQP1. Allergol Immunopathol (Madr). 2021;49:117–24. 10.15586/aei.v49i5.477
3. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA. 2005;294:813–8. 10.1001/jama.294.7.813
4. Thakar CV, Christianson A, Freyberg R, Almenoff P, Render ML. Incidence and outcomes of acute kidney injury in intensive care units: A veterans administration study. Crit Care Med. 2009;37:2552–8. 10.1097/CCM.0b013e3181a5906f
5. Murugan R, Kellum JA. Acute kidney injury: What’s the prognosis? Nat Rev Nephrol. 2011;7:209–17. 10.1038/nrneph.2011.13
6. Guo J, Wang R, Min F. Ginsenoside Rg1 ameliorates sepsis-induced acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells. J Leukoc Biol. 2022;112(5):1065–77. 10.1002/JLB.1A0422-211R
7. Chen Y, Jin S, Teng X, Hu Z, Zhang Z, Qiu X, et al. Hydrogen sulfide attenuates LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress. Oxid Med Cell Longev. 2018;2018:6717212. 10.1155/2018/6717212
8. Wang Z, Wu J, Hu Z, Luo C, Wang P, Zhang Y, et al. Dexmedetomidine alleviates lipopolysaccharide-induced acute kidney injury by inhibiting p75NTR-mediated oxidative stress and apoptosis. Oxid Med Cell Longev. 2020;2020:5454210. 10.1155/2020/5454210
9. Song C, Adili A, Kari A, Abuduhaer A. FSTL1 aggravates sepsis--induced acute kidney injury through regulating TLR4/MyD88/NF-κB pathway in newborn rats. Signa Vitae. 2021;17: 167–73.
10. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–247. 10.1007/s00134-021-06506-y
11. Keir I, Kellum JA. Acute kidney injury in severe sepsis: Pathophysiology, diagnosis, and treatment recommendations. J Vet Emerg Crit Care (San Antonio). 2015;25:200–9. 10.1111/vec.12297
12. Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 2019;96:1083–99. 10.1016/j.kint.2019.05.026
13. Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ. CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol. 2009;182:466–76. 10.4049/jimmunol.182.1.466
14. Kumar A, Tikoo S, Maity S, Sengupta S, Sengupta S, Kaur A, et al. Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione. EMBO Rep. 2012;13:1095–101. 10.1038/embor.2012.156
15. Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2013;1830:3143–53. 10.1016/j.bbagen.2012.09.008
16. Circu ML, Aw TY. Glutathione and apoptosis. Free Radic Res. 2008;42:689–706. 10.1080/10715760802317663
17. Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic Biol Med. 2020;152:175–85. 10.1016/j.freeradbiomed.2020.02.027
18. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article 3. 10.2202/1544-6115.1027
19. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist--oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523. 10.1038/s41467-019-09234-6
20. Deng Z, Sun M, Wu J, Fang H, Cai S, An S, et al. SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation. Cell Death Dis. 2021;12:217. 10.1038/s41419-021-03508-y
21. Fu Y, Jin R-R, Li Y-L, Luan H, Huang T, Zhao Y, et al. Isocorydine inhibits the proliferation of human endometrial carcinoma HEC-1B cells by downregulating the Ras/MEK/ERK signaling pathway. EJGO. 2021;42:548–53. 10.31083/j.ejgo.2021.03.5225
22. Chhabra R, Rao S, Kumar BM, Shetty AV, Hegde AM, Bhandary M. Characterization of stem cells from human exfoliated deciduous anterior teeth with varying levels of root resorption. J Clin Pediatr Dent. 2021;45:104–11. 10.17796/1053-4625-45.2.6
23. Liu Y, Li M, Shi D, Zhu Y. Higher expression of cation transport regulator-like protein 1 (CHAC1) predicts of poor outcomes in uveal melanoma (UM) patients. Int Ophthalmol. 2019;39:2825–32. 10.1007/s10792-019-01129-1
24. Goebel G, Berger R, Strasak AM, Egle D, Müller-Holzner E, Schmidt S, et al. Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients. Br J Cancer. 2012;106:189–98. 10.1038/bjc.2011.510
25. Gui Y, Sun L, Liu R, Luo J. Pachymic acid inhibits inflammation and cell apoptosis in lipopolysaccharide (LPS)-induced rat model with pneumonia by regulating NF-κB and MAPK pathways. Allergol Immunopathol (Madr). 2021;49:87–93. 10.15586/aei.v49i5.468
26. Pritam P, Manna S, Sahu A, Swain SS, Ramchandani S, Bissoyi S, et al. Eosinophil: A central player in modulating pathological complexity in asthma. Allergol Immunopathol (Madr). 2021;49:191–207. 10.15586/aei.v49i2.50
27. Zhu F, Yu Z, Li D. miR-187 Modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2. Signa Vitae. 2021;17:142–50. 10.21203/rs.3.rs-291355/v1
28. Zhu J, Xiong Y, Zhang Y, Wen J, Cai N, Cheng K, et al. The molecular mechanisms of regulating oxidative stress-induced ferroptosis and therapeutic strategy in tumors. Oxid Med Cell Longev. 2020;2020:8810785. 10.1155/2020/8810785
29. Jin Y, Sun L, Liu K-C. Effect of sufentanil on the viability and apoptosis of cervical cancer cells via the inactivation of PI3K/AKT/mTOR signaling pathway. Eur J Gynaecol Oncol. 2021;42:325–32. 10.31083/j.ejgo.2021.02.2257
30. Qian D, Zhu Y, Xu L, Dong T, Chen T, Yu Z. Icariin induces apoptosis in breast cancer MCF-7 cells by regulating the MELK-mediated PI3K/AKT signaling pathway. Eur J Gynaecol Oncol. 2021;42:957–65. 10.31083/j.ejgo4205144
31. Huang G, Bao J, Shao X, Zhou W, Wu B, Ni Z, et al. Inhibiting pannexin-1 alleviates sepsis-induced acute kidney injury via decreasing NLRP3 inflammasome activation and cell apoptosis. Life Sci. 2020;254:117791. 10.1016/j.lfs.2020.117791
32. Chen F, Wang W, Cai X, Yu H, Qu C, Zhang X, et al. Methyl jasmonate reduces the inflammation and apoptosis of HK-2 cells induced by LPS by regulating the NF-κB pathway. Signa Vitae. 2021;17:218–24.
33. Lu SJ, Xu JH, He ZF, Wu P, Ning C, Li HY. Innate immune molecule surfactant protein D attenuates sepsis-induced acute kidney injury through modulating apoptosis and NFκB-mediated inflammation. Int Wound J. 2020;17:100–06. 10.1111/iwj.13237
34. Nadeem A, Ahmad SF, Al-Harbi NO, Ibrahim KE, Alqahtani F, Alanazi WA, et al. Bruton’s tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice. Int Immunopharmacol. 2021;90:107123. 10.1016/j.intimp.2020.107123
35. Al-Harbi NO, Nadeem A, Ahmad SF, Alanazi MM, Aldossari AA, Alasmari F. Amelioration of sepsis-induced acute kidney injury through inhibition of inflammatory cytokines and oxidative stress in dendritic cells and neutrophils respectively in mice: Role of spleen tyrosine kinase signaling. Biochimie. 2019;158:102–10. 10.1016/j.biochi.2018.12.014
36. Liang NN, Zhao Y, Guo YY, Zhang ZH, Gao L, Yu DX, et al. Mitochondria-derived reactive oxygen species are involved in renal cell ferroptosis during lipopolysaccharide-induced acute kidney injury. Int Immunopharmacol. 2022;107:108687. 10.1016/j.intimp.2022.108687
37. Chen PH, Shen WL, Shih CM, Ho KH, Cheng CH, Lin CW, et al. The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology. 2017;116:300–14. 10.1016/j.neuropharm.2016.12.011
38. Duan X, Wen Z, Shen H, Shen M, Chen G. Intracerebral hemorrhage, oxidative stress, and antioxidant therapy. Oxid Med Cell Longev. 2016;2016:1203285. 10.1155/2016/1203285
39. Yu Y, Yan Y, Niu F, Wang Y, Chen X, Su G, et al. Ferroptosis: A cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov. 2021;7:193. 10.1038/s41420-021-00579-w
40. Cui Y, Li F, Zhu X, Xu J, Muhammad A, Chen Y, et al. Alfalfa saponins inhibit oxidative stress-induced cell apoptosis through the MAPK signaling pathway. Redox Rep. 2022;27:1–8. 10.1080/13510002.2021.2017681
41. Pang Z, Jiang Z, Zhu R, Song C, Tang H, Cao L, et al. Bardoxolone-methyl prevents oxidative stress-mediated apoptosis and extracellular matrix degradation in vitro and alleviates osteoarthritis in vivo. Drug Des Devel Ther. 2021;15:3735–47. 10.2147/DDDT.S314767
42. Lu S, Song Y, Luo R, Li S, Li G, Wang K, et al. Ferroportin-dependent iron homeostasis protects against oxidative stress-induced nucleus pulposus cell ferroptosis and ameliorates intervertebral disc degeneration in vivo. Oxid Med Cell Longev. 2021;2021:6670497. 10.1155/2021/6670497
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