{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T20:31:22Z","timestamp":1772829082693,"version":"3.50.1"},"reference-count":98,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["03Z22JN12"],"award-info":[{"award-number":["03Z22JN12"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["03COV07"],"award-info":[{"award-number":["03COV07"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Typical hemolytic uremic syndrome (HUS) can occur as a severe systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli. Its pathology can be induced by Stx types, resulting in toxin-mediated damage to renal barriers, inflammation, and the development of acute kidney injury (AKI). Two sphingosine kinase (SphK) isozymes, SphK1 and SphK2, have been shown to be involved in barrier maintenance and renal inflammatory diseases. Therefore, we sought to determine their role in the pathogenesis of HUS. Experimental HUS was induced by the repeated administration of Stx2 in wild-type (WT) and SphK1 (SphK1\u2212\/\u2212) or SphK2 (SphK2\u2212\/\u2212) null mutant mice. Disease severity was evaluated by assessing clinical symptoms, renal injury and dysfunction, inflammatory status and sphingolipid levels on day 5 of HUS development. Renal inflammation and injury were found to be attenuated in the SphK2\u2212\/\u2212 mice, but exacerbated in the SphK1\u2212\/\u2212 mice compared to the WT mice. The divergent outcome appeared to be associated with oppositely altered sphingolipid levels. This study represents the first description of the distinct roles of SphK1\u2212\/\u2212 and SphK2\u2212\/\u2212 in the pathogenesis of HUS. The identification of sphingolipid metabolism as a potential target for HUS therapy represents a significant advance in the field of HUS research.<\/jats:p>","DOI":"10.3390\/ijms25147683","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T16:23:41Z","timestamp":1720801421000},"page":"7683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deletion of Sphingosine Kinase 2 Attenuates Acute Kidney Injury in Mice with Hemolytic-Uremic Syndrome"],"prefix":"10.3390","volume":"25","author":[{"given":"Tina","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"ZIK Septomics Research Center, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Krieg","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"ZIK Septomics Research Center, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia I.","family":"Lange-Polovinkin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"ZIK Septomics Research Center, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianka","family":"Wissuwa","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"ZIK Septomics Research Center, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-7849","authenticated-orcid":false,"given":"Markus H.","family":"Gr\u00e4ler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"Center for Molecular Biomedicine (CMB) and Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07743 Jena, Germany"},{"name":"Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Dennhardt","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"ZIK Septomics Research Center, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7130-0006","authenticated-orcid":false,"given":"Sina M.","family":"Coldewey","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany"},{"name":"ZIK Septomics Research Center, Jena University Hospital, 07743 Jena, Germany"},{"name":"Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1086\/341940","article-title":"Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997\u20132000, in Germany and Austria: A prospective study","volume":"186","author":"Gerber","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_2","first-page":"e39347","article-title":"The Prevalence and Incidence of Hemolytic Uremic Syndrome: A Systematic Review","volume":"15","author":"Aldharman","year":"2023","journal-title":"Cureus"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e000465","DOI":"10.1136\/bmjpo-2019-000465","article-title":"Sociodemographic and clinical risk factors for paediatric typical haemolytic uraemic syndrome: Retrospective cohort study","volume":"3","author":"Adams","year":"2019","journal-title":"BMJ Paediatr. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1800068-43","DOI":"10.2807\/1560-7917.ES.2019.24.8.1800068","article-title":"Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016","volume":"24","author":"Bruyand","year":"2019","journal-title":"Eurosurveillance"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.jiac.2023.02.016","article-title":"Prognostic factors among patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: A retrospective cohort study using a nationwide inpatient database in Japan","volume":"29","author":"Myojin","year":"2023","journal-title":"J. Infect. Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1093\/aje\/kwt069","article-title":"Associations of Age and Sex with the Clinical Outcome and Incubation Period of Shiga toxin-producing Escherichia coli O104:H4 Infections, 2011","volume":"178","author":"Werber","year":"2013","journal-title":"Am. J. Epidemiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1385\/MB:26:2:117","article-title":"Infection by Shiga Toxin-Producing Escherichia coli: An Overview","volume":"26","author":"Karmali","year":"2004","journal-title":"Mol. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1056\/NEJMoa1106483","article-title":"Epidemic Profile of Shiga-Toxin\u2013Producing Escherichia coli O104:H4 Outbreak in Germany","volume":"365","author":"Frank","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/oxfordjournals.aje.a010082","article-title":"Massive Outbreak of Escherichia coli O157: H7 Infection In Schoolchildren in Sakai City, Japan, Associated with Consumption of White Radish Sprouts","volume":"150","author":"Michino","year":"1999","journal-title":"Am. J. Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3201\/eid1104.040739","article-title":"Epidemiology of Escherichia coli O157:H7 Outbreaks, United States, 1982\u20132002","volume":"11","author":"Rangel","year":"2005","journal-title":"Emerg. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"590","DOI":"10.3201\/eid2204.151485","article-title":"Shiga Toxin-Producing Escherichia coli O157, England and Wales, 1983\u20132012","volume":"22","author":"Adams","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S0140-6736(17)30062-4","article-title":"Haemolytic uraemic syndrome","volume":"390","author":"Fakhouri","year":"2017","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1128\/iai.53.1.135-140.1986","article-title":"Two toxin-converting phages from Escherichia coli O157:H7 strain 933 encode antigenically distinct toxins with similar biologic activities","volume":"53","author":"Strockbine","year":"1986","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.7883\/yoken1952.51.Supplement1_S5","article-title":"The Rediscovery of Shiga Toxin and Its Role in Clinical Disease","volume":"51","author":"Keusch","year":"1998","journal-title":"Jpn. J. Med. Sci. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S0140-6736(83)91795-6","article-title":"Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools","volume":"1","author":"Karmali","year":"1983","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1128\/iai.61.8.3392-3402.1993","article-title":"Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice","volume":"61","author":"Tesh","year":"1993","journal-title":"Infect. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1128\/JCM.00860-12","article-title":"Multicenter Evaluation of a Sequence-Based Protocol for Subtyping Shiga Toxins and Standardizing Stx Nomenclature","volume":"50","author":"Scheutz","year":"2012","journal-title":"J. Clin. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fruth, A., Lang, C., Gr\u00f6\u00dfl, T., Garn, T., and Flieger, A. (2024). Genomic surveillance of STEC\/EHEC infections in Germany 2020 to 2022 permits insight into virulence gene profiles and novel O-antigen gene clusters. Int. J. Med. Microbiol., 314.","DOI":"10.1016\/j.ijmm.2024.151610"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.33073\/pjm-2024-016","article-title":"Epidemiological Characteristics of Shiga Toxin-Producing Escherichia coli Responsible for Infections in the Polish Pediatric Population","volume":"73","author":"Wierzbicka","year":"2024","journal-title":"Pol. J. Microbiol."},{"key":"ref_20","first-page":"185","article-title":"Microbiological and serological control of Escherichia coli O157:H7 in kindergarten staff in Buenos Aires city and suburban areas","volume":"77","author":"Amaral","year":"2017","journal-title":"Medicina"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1093\/cid\/cis1218","article-title":"Duration of Fecal Shedding of Shiga Toxin\u2013Producing Escherichia coli O104:H4 in Patients Infected During the 2011 Outbreak in Germany: A Multicenter Study","volume":"56","author":"Vonberg","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1055\/s-0034-1376154","article-title":"Diagnosis and Treatment of the Hemolytic Uremic Syndrome Disease Spectrum in Developing Regions","volume":"40","author":"Hofer","year":"2014","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1007\/s00253-015-7236-3","article-title":"Shiga toxins: From structure and mechanism to applications","volume":"100","author":"Chan","year":"2015","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3390\/toxins3060626","article-title":"Shiga Toxin Interaction with Human Intestinal Epithelium","volume":"3","year":"2011","journal-title":"Toxins"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1084\/jem.163.6.1391","article-title":"Pathogenesis of shigella diarrhea. XI. Isolation of a shigella toxin-binding glycolipid from rabbit jejunum and HeLa cells and its identification as globotriaosylceramide","volume":"163","author":"Jacewicz","year":"1986","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1128\/iai.56.9.2373-2378.1988","article-title":"Direct cytotoxic action of Shiga toxin on human vascular endothelial cells","volume":"56","author":"Obrig","year":"1988","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1023\/A:1020299819637","article-title":"Verotoxin\/Globotriaosyl Ceramide Recognition: Angiopathy, Angiogenesis and Antineoplasia","volume":"19","author":"Lingwood","year":"1999","journal-title":"Biosci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1021\/bi971806n","article-title":"Structure of the Shiga-like Toxin I B-Pentamer Complexed with an Analogue of Its Receptor Gb3","volume":"37","author":"Ling","year":"1998","journal-title":"Biochemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/978-1-4899-1828-4_34","article-title":"Intracellular Transport and Processing of Protein Toxins Produced by Enteric Bacteria","volume":"412","author":"Sandvig","year":"1997","journal-title":"Mech. Pathog. Enteric Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1007\/s00467-020-04560-0","article-title":"Hemolytic uremic syndrome caused by Shiga toxin\u2013producing Escherichia coli in children: Incidence, risk factors, and clinical outcome","volume":"35","author":"Ylinen","year":"2020","journal-title":"Pediatr. Nephrol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.4049\/jimmunol.181.2.1460","article-title":"Fractalkine and CX3CR1 Mediate Leukocyte Capture by Endothelium in Response to Shiga Toxin","volume":"181","author":"Zanchi","year":"2008","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1128\/IAI.02120-14","article-title":"Differential Effects of Escherichia coli Subtilase Cytotoxin and Shiga Toxin 2 on Chemokine and Proinflammatory Cytokine Expression in Human Macrophage, Colonic Epithelial, and Brain Microvascular Endothelial Cell Lines","volume":"82","author":"Wang","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1189\/jlb.0308157","article-title":"Interactions between Shiga toxins and human polymorphonuclear leukocytes","volume":"84","author":"Brigotti","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8306","DOI":"10.1128\/IAI.73.12.8306-8316.2005","article-title":"Shiga Toxin 2 and Lipopolysaccharide Induce Human Microvascular Endothelial Cells To Release Chemokines and Factors That Stimulate Platelet Function","volume":"73","author":"Guessous","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1182\/blood.V97.10.3100","article-title":"Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome","volume":"97","author":"Karpman","year":"2001","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1128\/IAI.05139-11","article-title":"Differential Response of the Human Renal Proximal Tubular Epithelial Cell Line HK-2 to Shiga Toxin Types 1 and 2","volume":"79","author":"Lentz","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"M\u00e1rquez, L.B., Vel\u00e1zquez, N., Repetto, H.A., Paton, A.W., Paton, J.C., Ibarra, C., and Silberstein, C. (2014). Effects of Escherichia coli Subtilase Cytotoxin and Shiga Toxin 2 on Primary Cultures of Human Renal Tubular Epithelial Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087022"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.micpath.2016.08.010","article-title":"Effects of shiga toxin 2 on cellular regeneration mechanisms in primary and three-dimensional cultures of human renal tubular epithelial cells","volume":"99","author":"Araoz","year":"2016","journal-title":"Microb. Pathog."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/path.4388","article-title":"Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure","volume":"234","author":"Porubsky","year":"2014","journal-title":"J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.arcped.2023.09.016","article-title":"Kidney outcomes in Shiga toxin-associated hemolytic uremic syndrome in childhood: A retrospective single-center study from 1999 to 2017","volume":"31","author":"Viennet","year":"2024","journal-title":"Arch. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1007\/s00467-024-06355-z","article-title":"Outcome 10 years after Shiga toxin-producing E. coli (STEC)-associated hemolytic uremic syndrome: Importance of long-term follow-up","volume":"39","author":"Rosales","year":"2024","journal-title":"Pediatr. Nephrol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Weigel, C., Bellaci, J., and Spiegel, S. (2023). Sphingosine-1-phosphate and its receptors in vascular endothelial and lymphatic barrier function. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.104775"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"121404","DOI":"10.1016\/j.lfs.2023.121404","article-title":"Sphingosine-1-phosphate receptor 2 plays a dual role depending on the stage of cell differentiation in renal epithelial cells","volume":"316","author":"Romero","year":"2023","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1007\/s10620-010-1421-0","article-title":"Sphingosine-1-Phosphate Regulates the Expression of Adherens Junction Protein E-Cadherin and Enhances Intestinal Epithelial Cell Barrier Function","volume":"56","author":"Greenspon","year":"2010","journal-title":"Dig. Dis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Sun, G., Wang, B., Wu, X., Cheng, J., Ye, J., Wang, C., Zhu, H., and Liu, X. (2024). How do sphingosine-1-phosphate affect immune cells to resolve inflammation?. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1362459"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.cbpb.2012.05.006","article-title":"The control of the balance between ceramide and sphingosine-1-phosphate by sphingosine kinase: Oxidative stress and the seesaw of cell survival and death","volume":"163","author":"Williams","year":"2012","journal-title":"Comp. Biochem. Physiol. Part B Biochem. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.molmed.2011.03.002","article-title":"Translational aspects of sphingosine 1-phosphate biology","volume":"17","author":"Pyne","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tips.2017.04.003","article-title":"Sphingosine Kinase 2 in Autoimmune\/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors","volume":"38","author":"Pyne","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/nri2974","article-title":"The outs and the ins of sphingosine-1-phosphate in immunity","volume":"11","author":"Spiegel","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.prostaglandins.2012.06.002","article-title":"Analysis of sphingolipid and prostaglandin synthesis during zymosan-induced inflammation","volume":"99","author":"Linke","year":"2012","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1042\/BCJ20190730","article-title":"Mechanism of sphingosine 1-phosphate clearance from blood","volume":"477","author":"Kharel","year":"2020","journal-title":"Biochem. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7188","DOI":"10.1007\/s12035-019-1599-x","article-title":"Sphingosine Kinase-1 Is Essential for Maintaining External\/Outer Limiting Membrane and Associated Adherens Junctions in the Aging Retina","volume":"56","author":"Wilkerson","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Thuy, A.V., Reimann, C.-M., Ziegler, A.C., and Gr\u00e4ler, M.H. (2022). The Impact of Sphingosine Kinases on Inflammation-Induced Cytokine Release and Vascular Endothelial Barrier Integrity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112848"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1016\/j.ajpath.2017.06.017","article-title":"Sphingosine Kinase-2 Deficiency Ameliorates Kidney Fibrosis by Up-Regulating Smad7 in a Mouse Model of Unilateral Ureteral Obstruction","volume":"187","author":"Schwalm","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27594","DOI":"10.1038\/srep27594","article-title":"Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis","volume":"6","author":"Coldewey","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Weigel, C., H\u00fcttner, S.S., Ludwig, K., Krieg, N., Hofmann, S., Schr\u00f6der, N.H., Robbe, L., Kluge, S., Nierhaus, A., and Winkler, M.S. (2020). S1P lyase inhibition protects against sepsis by promoting disease tolerance via the S1P\/S1PR3 axis. EBioMedicine, 58.","DOI":"10.1016\/j.ebiom.2020.102898"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"F322","DOI":"10.1152\/ajprenal.00229.2021","article-title":"Loss of sphingosine kinase 2 protects against cisplatin-induced kidney injury","volume":"323","author":"Xie","year":"2022","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Ghosh, M., Thangada, S., Dasgupta, O., Khanna, K.M., Yamase, H.T., Kashgarian, M., Hla, T., Shapiro, L.H., and Ferrer, F.A. (2018). Cell-intrinsic sphingosine kinase 2 promotes macrophage polarization and renal inflammation in response to unilateral ureteral obstruction. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194053"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/ki.2008.400","article-title":"Divergent roles of sphingosine kinases in kidney ischemia\u2013reperfusion injury","volume":"75","author":"Jo","year":"2009","journal-title":"Kidney Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000502448","article-title":"Knockout of Sphingosine Kinase 1 Attenuates Renal Fibrosis in Unilateral Ureteral Obstruction Model","volume":"50","author":"Zhang","year":"2019","journal-title":"Am. J. Nephrol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Dennhardt, S., Pirschel, W., Wissuwa, B., Daniel, C., Gunzer, F., Lindig, S., Medyukhina, A., Kiehntopf, M., Rudolph, W.W., and Zipfel, P.F. (2018). Modeling Hemolytic-Uremic Syndrome: In-Depth Characterization of Distinct Murine Models Reflecting Different Features of Human Disease. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01459"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1128\/IAI.01264-13","article-title":"Oral Intoxication of Mice with Shiga Toxin Type 2a (Stx2a) and Protection by Anti-Stx2a Monoclonal Antibody 11E10","volume":"82","author":"Russo","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kr\u00f6ller, S., Wissuwa, B., Dennhardt, S., Krieg, N., Thiemermann, C., Daniel, C., Amann, K., Gunzer, F., and Coldewey, S.M. (2023). Bruton\u2019s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1105181"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.kint.2021.12.024","article-title":"Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin\u2013induced hemolytic-uremic syndrome in mice","volume":"101","author":"Pirschel","year":"2022","journal-title":"Kidney Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1046\/j.1523-1755.1998.00037.x","article-title":"Shiga toxin-induced tubular injury in hemolytic uremic syndrome","volume":"54","author":"Kaplan","year":"1998","journal-title":"Kidney Int."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1046\/j.1523-1755.2002.00502.x","article-title":"Differential tissue targeting and pathogenesis of verotoxins 1 and 2 in the mouse animal model","volume":"62","author":"Rutjes","year":"2002","journal-title":"Kidney Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/ped.14053","article-title":"Pathogenic functions and diagnostic utility of cytokines\/chemokines in EHEC-HUS","volume":"62","author":"Shimizu","year":"2019","journal-title":"Pediatr. Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40560-019-0376-2","article-title":"Loss of sphingosine 1-phosphate (S1P) in septic shock is predominantly caused by decreased levels of high-density lipoproteins (HDL)","volume":"7","author":"Winkler","year":"2019","journal-title":"J. Intensive Care"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4823","DOI":"10.1172\/JCI77685","article-title":"Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development","volume":"124","author":"Xiong","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/nature24053","article-title":"Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets","volume":"550","author":"Vu","year":"2017","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12086","DOI":"10.1038\/ncomms12086","article-title":"Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia","volume":"7","author":"Sun","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.semnephrol.2019.10.006","article-title":"Role of Renal Hypoxia in the Progression from Acute Kidney Injury to Chronic Kidney Disease","volume":"39","author":"Ullah","year":"2019","journal-title":"Semin. Nephrol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1164\/rccm.200309-1258OC","article-title":"Protective Effects of Sphingosine 1-Phosphate in Murine Endotoxin-induced Inflammatory Lung Injury","volume":"169","author":"Peng","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1164\/rccm.200405-684OC","article-title":"Sphingosine 1-Phosphate Reduces Vascular Leak in Murine and Canine Models of Acute Lung Injury","volume":"170","author":"McVerry","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1042\/BJ20120609","article-title":"Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate","volume":"447","author":"Kharel","year":"2012","journal-title":"Biochem. J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"15848","DOI":"10.1074\/jbc.M109.075549","article-title":"A Novel Function of Sphingosine Kinase 1 Suppression of JNK Activity in Preventing Inflammation and Injury","volume":"285","author":"Di","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1161\/01.RES.0000338501.84810.51","article-title":"Activation of Sphingosine Kinase-1 Reverses the Increase in Lung Vascular Permeability Through Sphingosine-1-Phosphate Receptor Signaling in Endothelial Cells","volume":"103","author":"Tauseef","year":"2008","journal-title":"Circ. Res."},{"key":"ref_78","first-page":"13","article-title":"Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: Implication of miRNAs and microvesicles","volume":"10","author":"Zhang","year":"2023","journal-title":"Mil. Med. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"106348","DOI":"10.1016\/j.prostaglandins.2019.106348","article-title":"Blood ceramides as novel markers for renal impairment in systemic lupus erythematosus","volume":"144","author":"Patyna","year":"2019","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jbior.2018.11.003","article-title":"The role of sphingolipids in acute kidney injury","volume":"70","author":"Dupre","year":"2018","journal-title":"Adv. Biol. Regul."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"F308","DOI":"10.1152\/ajprenal.00204.2004","article-title":"Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation","volume":"288","author":"Basnakian","year":"2005","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1681\/ASN.V12112384","article-title":"Role of Ceramide Synthase in Oxidant Injury to Renal Tubular Epithelial Cells","volume":"12","author":"Ueda","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1681\/ASN.V991670","article-title":"Ceramide accumulation during oxidant renal tubular injury","volume":"9","author":"Zager","year":"1998","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1681\/ASN.2020050697","article-title":"Sphingosine-1-Phosphate Metabolism and Signaling in Kidney Diseases","volume":"32","author":"Drexler","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1167\/iovs.17-22544","article-title":"Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy","volume":"59","author":"Eresch","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/BF00858440","article-title":"A clinicopathological study of 24 children with hemolytic uremic syndrome","volume":"4","author":"Argyle","year":"1990","journal-title":"Pediatr. Nephrol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1007\/s004670050337","article-title":"Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome","volume":"11","author":"Inward","year":"1997","journal-title":"Pediatr. Nephrol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1046\/j.1523-1755.1998.00118.x","article-title":"Shiga toxin-1 regulation of cytokine production by human proximal tubule cells","volume":"54","author":"Hughes","year":"1998","journal-title":"Kidney Int."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41385-019-0225-6","article-title":"Alpha-hemolysin of uropathogenic Escherichia coli induces GM-CSF-mediated acute kidney injury","volume":"13","author":"Wang","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-immunol-020711-075011","article-title":"Sphingosine-1-Phosphate and Lymphocyte Egress from Lymphoid Organs","volume":"30","author":"Cyster","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1681\/ASN.2016030306","article-title":"Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-\u03b3","volume":"28","author":"Bajwa","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5644","DOI":"10.4049\/jimmunol.179.9.5644","article-title":"Cutting Edge: Modulation of Intestinal Autoimmunity and IL-2 Signaling by Sphingosine Kinase 2 Independent of Sphingosine 1-Phosphate","volume":"179","author":"Samy","year":"2007","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1128\/IAI.01663-06","article-title":"Monocyte Chemoattractant Protein 1, Macrophage Inflammatory Protein 1\u03b1, and RANTES Recruit Macrophages to the Kidney in a Mouse Model of Hemolytic-Uremic Syndrome","volume":"75","author":"Keepers","year":"2007","journal-title":"Infect. Immun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"705","DOI":"10.7326\/0003-4819-109-9-705","article-title":"Illnesses Associated with Escherichia coli 0157:H7 Infections","volume":"109","author":"Griffin","year":"1988","journal-title":"Ann. Intern. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1128\/IAI.00060-09","article-title":"Shiga Toxin 2 Is Specifically Released from Bacterial Cells by Two Different Mechanisms","volume":"77","author":"Shimizu","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"52487","DOI":"10.1074\/jbc.M406512200","article-title":"Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720","volume":"279","author":"Allende","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"11113","DOI":"10.1128\/MCB.25.24.11113-11121.2005","article-title":"Essential Role for Sphingosine Kinases in Neural and Vascular Development","volume":"25","author":"Mizugishi","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"Faul","year":"2007","journal-title":"Behav. Res. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:16:11Z","timestamp":1760109371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,12]]},"references-count":98,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147683"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147683","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,12]]}}}