Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Ginsenoside Rg1 Suppresses Ferroptosis of Renal Tubular Epithelial Cells in Sepsis-induced Acute Kidney Injury via the FSP1-CoQ10- NAD(P)H Pathway

Author(s): Jun Guo*, Long Chen and Min Ma

Volume 31, Issue 15, 2024

Published on: 10 August, 2023

Page: [2119 - 2132] Pages: 14

DOI: 10.2174/0929867330666230607125054

Price: $65

Abstract

Introduction: Sepsis-induced acute kidney injury is related to an increased mortality rate by modulating ferroptosis through ginsenoside Rg1. In this study, we explored the specific mechanism of it.

Methods: Human renal tubular epithelial cells (HK-2) were transfected with oe-ferroptosis suppressor protein 1 and treated with lipopolysaccharide for ferroptosis induction, and they were then treated with ginsenoside Rg1 and ferroptosis suppressor protein 1 inhibitor. Ferroptosis suppressor protein 1, CoQ10, CoQ10H2, and intracellular NADH levels in HK-2 cells were assessed by Western blot, ELISA kit, and NAD/NADH kit. NAD+/NADH ratio was also calculated, and 4-Hydroxynonal fluorescence intensity was assessed by immunofluorescence. HK-2 cell viability and death were assessed by CCK-8 and propidium iodide staining. Ferroptosis, lipid peroxidation, and reactive oxygen species accumulation were assessed by Western blot, kits, flow cytometry, and C11 BODIPY 581/591 molecular probe. Sepsis rat models were established by cecal ligation and perforation to investigate whether ginsenoside Rg1 regulated the ferroptosis suppressor protein 1-CoQ10-NAD(P)H pathway in vivo.

Results: LPS treatment diminished ferroptosis suppressor protein 1, CoQ10, CoQ10H2, and NADH contents in HK-2 cells, while facilitating NAD+/NADH ratio and relative 4- Hydroxynonal fluorescence intensity. FSP1 overexpression inhibited lipopolysaccharideinduced lipid peroxidation in HK-2 cells via the ferroptosis suppressor protein 1-CoQ10- NAD(P)H pathway. The ferroptosis suppressor protein 1-CoQ10-NAD(P)H pathway suppressed lipopolysaccharide-induced ferroptosis in HK-2 cells. Ginsenoside Rg1 alleviated ferroptosis in HK-2 cells by regulating the ferroptosis suppressor protein 1-CoQ10- NAD(P)H pathway. Moreover, ginsenoside Rg1 regulated the ferroptosis suppressor protein 1-CoQ10-NAD(P)H pathway in vivo.

Conclusion: Ginsenoside Rg1 alleviated sepsis-induced acute kidney injury by blocking renal tubular epithelial cell ferroptosis via the ferroptosis suppressor protein 1-CoQ10- NAD(P)H pathway.

Keywords: Sepsis, acute kidney injury, ginsenoside Rg1, ferroptosis FSP1-CoQ10-NAD(P)H pathway, HK-2 cells, lipopolysaccharide, 4-HNE.

« Previous
[1]
van der Poll, T.; van de Veerdonk, F.L.; Scicluna, B.P.; Netea, M.G. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol., 2017, 17(7), 407-420.
[http://dx.doi.org/10.1038/nri.2017.36] [PMID: 28436424]
[2]
Rello, J.; Valenzuela-Sánchez, F.; Ruiz-Rodriguez, M.; Moyano, S. Sepsis: A review of advances in management. Adv. Ther., 2017, 34(11), 2393-2411.
[http://dx.doi.org/10.1007/s12325-017-0622-8] [PMID: 29022217]
[3]
Lelubre, C.; Vincent, J.L. Mechanisms and treatment of organ failure in sepsis. Nat. Rev. Nephrol., 2018, 14(7), 417-427.
[http://dx.doi.org/10.1038/s41581-018-0005-7] [PMID: 29691495]
[4]
Bellomo, R.; Kellum, J.A.; Ronco, C.; Wald, R.; Martensson, J.; Maiden, M.; Bagshaw, S.M.; Glassford, N.J.; Lankadeva, Y.; Vaara, S.T.; Schneider, A. Acute kidney injury in sepsis. Intensive Care Med., 2017, 43(6), 816-828.
[http://dx.doi.org/10.1007/s00134-017-4755-7] [PMID: 28364303]
[5]
Manrique-Caballero, C.L.; Del Rio-Pertuz, G.; Gomez, H. Sepsis-associated acute kidney injury. Crit. Care Clin., 2021, 37(2), 279-301.
[http://dx.doi.org/10.1016/j.ccc.2020.11.010] [PMID: 33752856]
[6]
Tan, C.; Gu, J.; Li, T.; Chen, H.; Liu, K.; Liu, M.; Zhang, H.; Xiao, X. Inhibition of aerobic glycolysis alleviates sepsis-induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK-regulated autophagy. Int. J. Mol. Med., 2021, 47(3), 19.
[http://dx.doi.org/10.3892/ijmm.2021.4852] [PMID: 33448325]
[7]
Guo, J.; Wang, R.; Liu, D. Bone marrow-derived mesenchymal stem cells ameliorate sepsis-induced acute kidney injury by promoting mitophagy of renal tubular epithelial cells via the SIRT1/Parkin axis. Front. Endocrinol., 2021, 12, 639165.
[http://dx.doi.org/10.3389/fendo.2021.639165] [PMID: 34248837]
[8]
Kellum, J.A.; Fuhrman, D.Y. The handwriting is on the wall: There will soon be a drug for AKI. Nat. Rev. Nephrol., 2019, 15(2), 65-66.
[http://dx.doi.org/10.1038/s41581-018-0095-2] [PMID: 30546091]
[9]
Emlet, D.R.; Shaw, A.D.; Kellum, J.A.; Sepsis-associated, A.K.I. Sepsis-associated AKI: Epithelial cell dysfunction. Semin. Nephrol., 2015, 35(1), 85-95.
[http://dx.doi.org/10.1016/j.semnephrol.2015.01.009] [PMID: 25795502]
[10]
Post, E.H.; Kellum, J.A.; Bellomo, R.; Vincent, J.L. Renal perfusion in sepsis: From macro- to microcirculation. Kidney Int., 2017, 91(1), 45-60.
[http://dx.doi.org/10.1016/j.kint.2016.07.032] [PMID: 27692561]
[11]
Jang, H.R.; Rabb, H. Immune cells in experimental acute kidney injury. Nat. Rev. Nephrol., 2015, 11(2), 88-101.
[http://dx.doi.org/10.1038/nrneph.2014.180] [PMID: 25331787]
[12]
Sureshbabu, A.; Patino, E.; Ma, K.C.; Laursen, K.; Finkelsztein, E.J.; Akchurin, O.; Muthukumar, T.; Ryter, S.W.; Gudas, L.; Choi, A.M.K.; Choi, M.E. RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction. JCI Insight, 2018, 3(11), e98411.
[http://dx.doi.org/10.1172/jci.insight.98411] [PMID: 29875323]
[13]
Kumar, S. Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int., 2018, 93(1), 27-40.
[http://dx.doi.org/10.1016/j.kint.2017.07.030] [PMID: 29291820]
[14]
Thomas, K.; Zondler, L.; Ludwig, N.; Kardell, M.; Lüneburg, C.; Henke, K.; Mersmann, S.; Margraf, A.; Spieker, T.; Tekath, T.; Velic, A.; Holtmeier, R.; Hermann, J.; Jankowski, V.; Meersch, M.; Vestweber, D.; Westphal, M.; Roth, J.; Schäfers, M.A.; Kellum, J.A.; Lowell, C.A.; Rossaint, J.; Zarbock, A. Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells. JCI Insight, 2022, 7(21), e163161.
[http://dx.doi.org/10.1172/jci.insight.163161] [PMID: 36107633]
[15]
Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; Morrison, B., III; Stockwell, B.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID: 22632970]
[16]
Jiang, X.; Stockwell, B.R.; Conrad, M. Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol., 2021, 22(4), 266-282.
[http://dx.doi.org/10.1038/s41580-020-00324-8] [PMID: 33495651]
[17]
Li, N.; Wang, W.; Zhou, H.; Wu, Q.; Duan, M.; Liu, C.; Wu, H.; Deng, W.; Shen, D.; Tang, Q. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radic. Biol. Med., 2020, 160, 303-318.
[http://dx.doi.org/10.1016/j.freeradbiomed.2020.08.009] [PMID: 32846217]
[18]
Li, J.; Ren, C.; Wang, L.X.; Yao, R.; Dong, N.; Wu, Y.; Tian, Y.; Yao, Y. Sestrin2 protects dendrite cells against ferroptosis induced by sepsis. Cell Death Dis., 2021, 12(9), 834.
[http://dx.doi.org/10.1038/s41419-021-04122-8] [PMID: 34482365]
[19]
Hosohata, K.; Harnsirikarn, T.; Chokesuwattanaskul, S. Ferroptosis: A potential therapeutic target in acute kidney injury. Int. J. Mol. Sci., 2022, 23(12), 6583.
[http://dx.doi.org/10.3390/ijms23126583] [PMID: 35743026]
[20]
Hu, J.; Gu, W.; Ma, N.; Fan, X.; Ci, X. Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway. Br. J. Pharmacol., 2022, 179(15), 3991-4009.
[http://dx.doi.org/10.1111/bph.15834] [PMID: 35303762]
[21]
Li, D.; Liu, B.; Fan, Y.; Liu, M.; Han, B.; Meng, Y.; Xu, X.; Song, Z.; Liu, X.; Hao, Q.; Duan, X.; Nakai, A.; Chang, Y.; Cao, P.; Tan, K. Nuciferine protects against folic acid-induced acute kidney injury by inhibiting ferroptosis. Br. J. Pharmacol., 2021, 178(5), 1182-1199.
[http://dx.doi.org/10.1111/bph.15364] [PMID: 33450067]
[22]
Kim, D.H.; Choi, H.I.; Park, J.S.; Kim, C.S.; Bae, E.H.; Ma, S.K.; Kim, S.W. Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes. Redox Biol., 2022, 54, 102382.
[http://dx.doi.org/10.1016/j.redox.2022.102382] [PMID: 35767918]
[23]
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), 1065-1077.
[http://dx.doi.org/10.1002/JLB.1A0422-211R] [PMID: 35774015]
[24]
Sun, M.; Ye, Y.; Xiao, L.; Duan, X.; Zhang, Y.; Zhang, H. Anticancer effects of ginsenoside Rg3 (Review). Int. J. Mol. Med., 2017, 39(3), 507-518.
[http://dx.doi.org/10.3892/ijmm.2017.2857] [PMID: 28098857]
[25]
Liu, Z.; Pan, H.; Zhang, Y.; Zheng, Z.; Xiao, W.; Hong, X.; Chen, F.; Peng, X.; Pei, Y.; Rong, J.; He, J.; Zou, L.; Wang, J.; Zhong, J.; Han, X.; Cao, Y. Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3β signaling pathway. J. Biochem. Mol. Toxicol., 2022, 36(1), e22885.
[http://dx.doi.org/10.1002/jbt.22885] [PMID: 34859534]
[26]
Ni, X.J.; Xu, Z.Q.; Jin, H.; Zheng, S.L.; Cai, Y.; Wang, J.J. Ginsenoside Rg1 protects human renal tubular epithelial cells from lipopolysaccharide-induced apoptosis and inflammation damage. Braz. J. Med. Biol. Res., 2018, 51(2), e6611.
[http://dx.doi.org/10.1590/1414-431x20176611] [PMID: 29267498]
[27]
Mishima, E.; Ito, J.; Wu, Z.; Nakamura, T.; Wahida, A.; Doll, S.; Tonnus, W.; Nepachalovich, P.; Eggenhofer, E.; Aldrovandi, M.; Henkelmann, B.; Yamada, K.; Wanninger, J.; Zilka, O.; Sato, E.; Feederle, R.; Hass, D.; Maida, A.; Mourão, A.S.D.; Linkermann, A.; Geissler, E.K.; Nakagawa, K.; Abe, T.; Fedorova, M.; Proneth, B.; Pratt, D.A.; Conrad, M. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature, 2022, 608(7924), 778-783.
[http://dx.doi.org/10.1038/s41586-022-05022-3] [PMID: 35922516]
[28]
Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Goya Grocin, A.; Xavier da Silva, T.N.; Panzilius, E.; Scheel, C.H.; Mourão, A.; Buday, K.; Sato, M.; Wanninger, J.; Vignane, T.; Mohana, V.; Rehberg, M.; Flatley, A.; Schepers, A.; Kurz, A.; White, D.; Sauer, M.; Sattler, M.; Tate, E.W.; Schmitz, W.; Schulze, A.; O’Donnell, V.; Proneth, B.; Popowicz, G.M.; Pratt, D.A.; Angeli, J.P.F.; Conrad, M. FSP1 is a glutathione-independent ferroptosis suppressor. Nature, 2019, 575(7784), 693-698.
[http://dx.doi.org/10.1038/s41586-019-1707-0] [PMID: 31634899]
[29]
Ye, M.; Zhao, Y.; Wang, Y.; Xie, R.; Tong, Y.; Sauer, J.D.; Gong, S. NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis. Nat. Nanotechnol., 2022, 17(8), 880-890.
[http://dx.doi.org/10.1038/s41565-022-01137-w] [PMID: 35668170]
[30]
Yang, H.; Du, L.; Zhang, Z. Potential biomarkers in septic shock besides lactate. Exp. Biol. Med., 2020, 245(12), 1066-1072.
[http://dx.doi.org/10.1177/1535370220919076] [PMID: 32276542]
[31]
Pagano, G.; Manfredi, C.; Pallardó, F.V.; Lyakhovich, A.; Tiano, L.; Trifuoggi, M. Potential roles of mitochondrial cofactors in the adjuvant mitigation of proinflammatory acute infections, as in the case of sepsis and COVID-19 pneumonia. Inflamm. Res., 2021, 70(2), 159-170.
[http://dx.doi.org/10.1007/s00011-020-01423-0] [PMID: 33346851]
[32]
Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; Bassik, M.C.; Nomura, D.K.; Dixon, S.J.; Olzmann, J.A. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature, 2019, 575(7784), 688-692.
[http://dx.doi.org/10.1038/s41586-019-1705-2] [PMID: 31634900]
[33]
Yang, M.; Tsui, M.G.; Tsang, J.K.W.; Goit, R.K.; Yao, K.M.; So, K.F.; Lam, W.C.; Lo, A.C.Y. Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis. Cell Death Dis., 2022, 13(5), 468.
[http://dx.doi.org/10.1038/s41419-022-04924-4] [PMID: 35585057]
[34]
Luo, Y.; Hao, T.; Zhang, J.; Zhang, M.; Sun, P.; Wu, L. MicroRNA-592 suppresses the malignant phenotypes of thyroid cancer by regulating lncRNA NEAT1 and downregulating NOVA1. Int. J. Mol. Med., 2019, 44(3), 1172-1182.
[http://dx.doi.org/10.3892/ijmm.2019.4278] [PMID: 31524231]
[35]
Gómez, H.; Kellum, J.A. Sepsis-induced acute kidney injury. Curr. Opin. Crit. Care, 2016, 22(6), 546-553.
[http://dx.doi.org/10.1097/MCC.0000000000000356] [PMID: 27661757]
[36]
Li, Y.; Wang, F.; Luo, Y. Ginsenoside Rg1 protects against sepsis-associated encephalopathy through beclin 1–independent autophagy in mice. J. Surg. Res., 2017, 207, 181-189.
[http://dx.doi.org/10.1016/j.jss.2016.08.080] [PMID: 27979475]
[37]
Wang, Q.L.; Yang, L.; Peng, Y.; Gao, M.; Yang, M.S.; Xing, W.; Xiao, X.Z. Ginsenoside Rg1 regulates SIRT1 to ameliorate sepsis-induced lung inflammation and injury via inhibiting endoplasmic reticulum stress and inflammation. Mediators Inflamm., 2019, 2019, 1-10.
[http://dx.doi.org/10.1155/2019/6453296] [PMID: 30918470]
[38]
Wang, B.; Wang, Y.; Xu, K.; Zeng, Z.; Xu, Z.; Yue, D.; Li, T.; Luo, J.; Liu, J.; Yuan, J. Resveratrol alleviates sepsis-induced acute kidney injury by deactivating the lncRNA MALAT1/MiR-205 axis. Cent. Eur. J. Immunol., 2021, 46(3), 295-304.
[http://dx.doi.org/10.5114/ceji.2021.109195] [PMID: 34764801]
[39]
Rousta, A.M.; Mirahmadi, S.M.S.; Shahmohammadi, A.; Nourabadi, D.; Khajevand-Khazaei, M.R.; Baluchnejadmojarad, T.; Roghani, M. Protective effect of sesamin in lipopolysaccharide-induced mouse model of acute kidney injury via attenuation of oxidative stress, inflammation, and apoptosis. Immunopharmacol. Immunotoxicol., 2018, 40(5), 423-429.
[http://dx.doi.org/10.1080/08923973.2018.1523926] [PMID: 30488751]
[40]
Liang, N.N.; Zhao, Y.; Guo, Y.Y.; Zhang, Z.H.; Gao, L.; Yu, D.X.; Xu, D.X.; Xu, S. Mitochondria-derived reactive oxygen species are involved in renal cell ferroptosis during lipopolysaccharide-induced acute kidney injury. Int. Immunopharmacol., 2022, 107, 108687.
[http://dx.doi.org/10.1016/j.intimp.2022.108687] [PMID: 35279512]
[41]
Tonnus, W.; Meyer, C.; Steinebach, C.; Belavgeni, A.; von Mässenhausen, A.; Gonzalez, N.Z.; Maremonti, F.; Gembardt, F.; Himmerkus, N.; Latk, M.; Locke, S.; Marschner, J.; Li, W.; Short, S.; Doll, S.; Ingold, I.; Proneth, B.; Daniel, C.; Kabgani, N.; Kramann, R.; Motika, S.; Hergenrother, P.J.; Bornstein, S.R.; Hugo, C.; Becker, J.U.; Amann, K.; Anders, H.J.; Kreisel, D.; Pratt, D.; Gütschow, M.; Conrad, M.; Linkermann, A. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat. Commun., 2021, 12(1), 4402.
[http://dx.doi.org/10.1038/s41467-021-24712-6] [PMID: 34285231]
[42]
Koppula, P.; Lei, G.; Zhang, Y.; Yan, Y.; Mao, C.; Kondiparthi, L.; Shi, J.; Liu, X.; Horbath, A.; Das, M.; Li, W.; Poyurovsky, M.V.; Olszewski, K.; Gan, B. A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat. Commun., 2022, 13(1), 2206.
[http://dx.doi.org/10.1038/s41467-022-29905-1] [PMID: 35459868]
[43]
Park, M.W.; Cha, H.W.; Kim, J.; Kim, J.H.; Yang, H.; Yoon, S.; Boonpraman, N.; Yi, S.S.; Yoo, I.D.; Moon, J.S. NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases. Redox Biol., 2021, 41, 101947.
[http://dx.doi.org/10.1016/j.redox.2021.101947] [PMID: 33774476]
[44]
Chen, R.; Zhu, S.; Zeng, L.; Wang, Q.; Sheng, Y.; Zhou, B.; Tang, D.; Kang, R. AGER-mediated lipid peroxidation drives caspase-11 inflammasome activation in sepsis. Front. Immunol., 2019, 10, 1904.
[http://dx.doi.org/10.3389/fimmu.2019.01904] [PMID: 31440260]
[45]
Santoro, M.M. The antioxidant role of non-mitochondrial CoQ10: Mystery ld! Cell Metab., 2020, 31(1), 13-15.
[http://dx.doi.org/10.1016/j.cmet.2019.12.007] [PMID: 31951565]

Rights & Permissions Print Cite
Article Metrics
40
2
© 2024 Bentham Science Publishers | Privacy Policy