Abstract
Ferroptosis is a predominant contributor to renal ischemia reperfusion injury (IRI) after kidney transplant, evoking delayed graft function and poorer long-term outcomes. The wide propagation of ferroptosis among cell populations in a wave-like manner, developing the “wave of ferroptosis” causes a larger area of tubular necrosis and accordingly aggravates renal allograft IRI. In this study, we decipher a whole new metabolic mechanism underlying ferroptosis and propose a novel spreading pathway of the “wave of ferroptosis” in the renal tissue microenvironment, in which renal IRI cell-secreted small extracellular vesicles (IRI-sEVs) delivering lncRNA WAC-AS1 reprogram glucose metabolism in adjacent renal tubular epithelial cell populations by inducing GFPT1 expression and increasing hexosamine biosynthesis pathway (HBP) flux, and consequently enhances O-GlcNAcylation. Additionally, BACH2 O-GlcNAcylation at threonine 389 in renal tubular epithelial cells prominently inhibits its degradation by ubiquitination and promotes importin α5-mediated nuclear translocation. We present the first evidence that intranuclear BACH2 suppresses SLC7A11 and GPX4 transcription by binding to their proximal promoters and decreases cellular anti-peroxidation capability, accordingly facilitating ferroptosis. Inhibition of sEV biogenesis and secretion by GW4869 and knockout of lncRNA WAC-AS1 in IRI-sEVs both unequivocally diminished the “wave of ferroptosis” propagation and protected against renal allograft IRI. The functional and mechanistic regulation of IRI-sEVs was further corroborated in an allograft kidney transplant model and an in situ renal IRI model. In summary, these findings suggest that inhibiting sEV-mediated lncRNA WAC-AS1 secretion and targeting HBP metabolism-induced BACH2 O-GlcNAcylation in renal tubular epithelial cells may serve as new strategies for protecting against graft IRI after kidney transplant.
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References
Chen W, Wang L, Liang P, Mast J, Mathis C, Liu CY, et al. Reducing ischemic kidney injury through application of a synchronization modulation electric field to maintain Na(+)/K(+)-ATPase functions. Sci Transl Med. 2022;14:eabj4906.
Zhu J, Zhang G, Song Z, Xiang X, Shu S, Liu Z, et al. Protein kinase C-δ mediates kidney tubular injury in cold storage-associated kidney transplantation. J Am Soc Nephrol. 2020;31:1050–65.
Xu-Dubois YC, Ahmadpoor P, Brocheriou I, Louis K, Arzouk Snanoudj N, Rouvier P, et al. Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts. Am J Transplant. 2020;20:2400–12.
Thompson ER, Bates L, Ibrahim IK, Sewpaul A, Stenberg B, McNeill A, et al. Novel delivery of cellular therapy to reduce ischemia reperfusion injury in kidney transplantation. Am J Transplant. 2021;21:1402–14.
Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Mässenhausen A, Gonzalez NZ, et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat Commun. 2021;12:4402.
Belavgeni A, Meyer C, Stumpf J, Hugo C, Linkermann A. Ferroptosis and necroptosis in the kidney. Cell Chem Biol. 2020;27:448–62.
Riegman M, Bradbury MS, Overholtzer M. Population dynamics in cell death: mechanisms of propagation. Trends Cancer. 2019;5:558–68.
Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA. 2014;111:16836–41.
Martin-Sanchez D, Fontecha-Barriuso M, Carrasco S, Sanchez-Niño MD, Mässenhausen AV, Linkermann A, et al. TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proc Natl Acad Sci USA. 2018;115:4182–7.
Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15:135–47.
Riegman M, Sagie L, Galed C, Levin T, Steinberg N, Dixon SJ, et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat Cell Biol. 2020;22:1042–8.
Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu H, Zhu LJ, et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell. 2019;51:575–86.e574.
van Niel G, Carter DRF, Clayton A, Lambert DW, Raposo G, Vader P. Challenges and directions in studying cell-cell communication by extracellular vesicles. Nat Rev Mol cell Biol. 2022;23:369–82.
van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64:676–705.
Huang D, Sun G, Hao X, He X, Zheng Z, Chen C et al. ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression. J Clin Invest. 2021;131:e138986.
Liu W, Tang P, Wang J, Ye W, Ge X, Rong Y, et al. Extracellular vesicles derived from melatonin-preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2. J Pineal Res. 2021;71:e12769.
Zhao H, Chen X, Hu G, Li C, Guo L, Zhang L, et al. Small extracellular vesicles from brown adipose tissue mediate exercise cardioprotection. Circulation Res. 2022;130:1490–506.
Gan L, Xie D, Liu J, Bond Lau W, Christopher TA, Lopez B, et al. Small extracellular microvesicles mediated pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanism exacerbating ischemia/reperfusion injury in diabetic mice. Circulation. 2020;141:968–83.
Ge X, Meng Q, Wei L, Liu J, Li M, Liang X, et al. Myocardial ischemia-reperfusion induced cardiac extracellular vesicles harbour proinflammatory features and aggravate heart injury. J Extracell Vesicles. 2021;10:e12072.
Liu J, Peng Y, Shi L, Wan L, Inuzuka H, Long J, et al. Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res. 2021;31:80–93.
Marchiq I, Le Floch R, Roux D, Simon MP, Pouyssegur J. Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Res. 2015;75:171–80.
Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019;73:354–63.e353.
Leu JI, Murphy ME, George DL. Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of TP53. Proc Natl Acad Sci USA. 2020;117:26804–11.
Stincone A, Prigione A, Cramer T, Wamelink MM, Campbell K, Cheung E, et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc. 2015;90:927–63.
Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308.
Yan B, Ai Y, Sun Q, Ma Y, Cao Y, Wang J, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol cell. 2021;81:355–69.e310.
Lam C, Low JY, Tran PT, Wang H. The hexosamine biosynthetic pathway and cancer: current knowledge and future therapeutic strategies. Cancer Lett. 2021;503:11–18.
Gélinas R, Mailleux F, Dontaine J, Bultot L, Demeulder B, Ginion A, et al. AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. Nat Commun. 2018;9:374.
Mapanga RF, Joseph D, Symington B, Garson KL, Kimar C, Kelly-Laubscher R, et al. Detrimental effects of acute hyperglycaemia on the rat heart. Acta Physiologica. 2014;210:546–64.
Mapanga RF, Essop MF. Damaging effects of hyperglycemia on cardiovascular function: spotlight on glucose metabolic pathways. Am J Physiol Heart Circulatory Physiol. 2016;310:H153–173.
Cong R, Sun L, Yang J, Cui H, Ji X, Zhu J, et al. Protein O-GlcNAcylation alleviates small intestinal injury induced by ischemia-reperfusion and oxygen-glucose deprivation. Biomed Pharmacother. 2021;138:111477.
Li X, Peng X, Zhang C, Bai X, Li Y, Chen G, et al. Bladder cancer-derived small extracellular vesicles promote tumor angiogenesis by inducing HBP-related metabolic reprogramming and SerRS O-GlcNAcylation in endothelial cells. Adv Sci. 2022;9:e2202993.
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750.
Dhondt B, Geeurickx E, Tulkens J, Van Deun J, Vergauwen G, Lippens L, et al. Unravelling the proteomic landscape of extracellular vesicles in prostate cancer by density-based fractionation of urine. J Extracell Vesicles. 2020;9:1736935.
Jingushi K, Uemura M, Ohnishi N, Nakata W, Fujita K, Naito T, et al. Extracellular vesicles isolated from human renal cell carcinoma tissues disrupt vascular endothelial cell morphology via azurocidin. Int J cancer. 2018;142:607–17.
Guo J, Wu C, Lin X, Zhou J, Zhang J, Zheng W, et al. Establishment of a simplified dichotomic size-exclusion chromatography for isolating extracellular vesicles toward clinical applications. J Extracell Vesicles. 2021;10:e12145.
Li X, Wei Z, Yu H, Xu Y, He W, Zhou X, et al. Secretory autophagy-induced bladder tumour-derived extracellular vesicle secretion promotes angiogenesis by activating the TPX2-mediated phosphorylation of the AURKA-PI3K-AKT axis. Cancer Lett. 2021;523:10–28.
Minami K, Bae S, Uehara H, Zhao C, Lee D, Iske J, et al. Targeting of intragraft reactive oxygen species by APP-103, a novel polymer product, mitigates ischemia/reperfusion injury and promotes the survival of renal transplants. Am J Transplant. 2020;20:1527–37.
Yoshida C, Yoshida F, Sears DE, Hart SM, Ikebe D, Muto A, et al. Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1. Blood. 2007;109:1211–9.
Zhou Y, Wu H, Zhao M, Chang C, Lu Q. The Bach family of transcription factors: a comprehensive review. Clin Rev allergy Immunol. 2016;50:345–56.
Kono K, Harano Y, Hoshino H, Kobayashi M, Bazett-Jones DP, Muto A, et al. The mobility of Bach2 nuclear foci is regulated by SUMO-1 modification. Exp Cell Res. 2008;314:903–13.
Hoshino H, Kobayashi A, Yoshida M, Kudo N, Oyake T, Motohashi H, et al. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J Biol Chem. 2000;275:15370–6.
Nishizawa H, Matsumoto M, Chen G, Ishii Y, Tada K, Onodera M, et al. Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells. Cell Death Dis. 2021;12:332.
Wang J, Liu Y, Wang Y, Sun L. The cross-link between ferroptosis and kidney diseases. Oxid Med Cell Longev. 2021;2021:6654887.
Linkermann A, Hackl MJ, Kunzendorf U, Walczak H, Krautwald S, Jevnikar AM. Necroptosis in immunity and ischemia-reperfusion injury. Am J Transplant. 2013;13:2797–804.
Katikaneni A, Jelcic M, Gerlach GF, Ma Y, Overholtzer M, Niethammer P. Lipid peroxidation regulates long-range wound detection through 5-lipoxygenase in zebrafish. Nat Cell Biol. 2020;22:1049–55.
Kim SE, Zhang L, Ma K, Riegman M, Chen F, Ingold I, et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol. 2016;11:977–85.
Urabe F, Patil K, Ramm GA, Ochiya T, Soekmadji C. Extracellular vesicles in the development of organ-specific metastasis. J Extracell Vesicles. 2021;10:e12125.
Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84.
Park EJ, Shimaoka M. Integrin-mediated exosomal homing to organs. Methods Mol Biol. 2023;2668:145–58.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.
Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022;82:2215–27.
Yao X, Li W, Fang D, Xiao C, Wu X, Li M, et al. Emerging roles of energy metabolism in ferroptosis regulation of tumor cells. Adv Sci. 2021;8:e2100997.
Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab. 2020;32:920–37.
Wang X, Lu S, He C, Wang C, Wang L, Piao M, et al. RSL3 induced autophagic death in glioma cells via causing glycolysis dysfunction. Biochem Biophys Res Commun. 2019;518:590–7.
Prakoso D, Lim SY, Erickson JR, Wallace RS, Lees JG, Tate M, et al. Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart. Cardiovasc Res. 2022;118:212–25.
Fülöp N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, et al. Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol Cell Physiol. 2007;292:C1370–8.
Ou W, Liang Y, Qin Y, Wu W, Xie M, Zhang Y, et al. Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation. Redox Biol. 2021;43:101994.
Hoshino H, Igarashi K. Expression of the oxidative stress-regulated transcription factor bach2 in differentiating neuronal cells. J Biochem. 2002;132:427–31.
Suzuki H, Tashiro S, Sun J, Doi H, Satomi S, Igarashi K. Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene. J Biol Chem. 2003;278:49246–53.
Acknowledgements
We appreciate Researcher Xin Liu at the CAS Centre for Excellence in Molecular Cell Science for the technical assistance. We also thank the New Talent Program initiated by Chongqing Medical University. This work was supported by the National Natural Science Foundation of China under Grant (number: 81874092) and Chongqing Science and Technology Bureau under Grant (number: cstc2019jscx-dxwtBX0018).
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Conceptualization: XL; Methodology: XL, XP and XZ; Investigation: XL, XP, ML, GC, WS, HY, CZ, YL and ZF; Writing-Original Draft: XL; Funding Acquisition: WH and XG; Resources: SL, WH and XG; Supervision: WH and XG; Revision: XL, XZ and JL.
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The study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (181). The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the "Declaration of Istanbul on Organ Trafficking and Transplant Tourism". All animal experimental protocols and care procedures conformed to the Chongqing Medical University of Medicine Policy on the Care and Use of Laboratory Animals (k276).
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Li, X., Peng, X., Zhou, X. et al. Small extracellular vesicles delivering lncRNA WAC-AS1 aggravate renal allograft ischemia‒reperfusion injury by inducing ferroptosis propagation. Cell Death Differ 30, 2167–2186 (2023). https://doi.org/10.1038/s41418-023-01198-x
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DOI: https://doi.org/10.1038/s41418-023-01198-x
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