{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T12:04:36Z","timestamp":1792929876375,"version":"4.5.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T00:00:00Z","timestamp":1655164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/17\/69\/33484"],"award-info":[{"award-number":["FS\/17\/69\/33484"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. <jats:italic>In vitro<\/jats:italic>, RG100204 blocked mouse AQP9 H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg\/kg p.o. before CLP and then again at 8\u00a0h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3\u00a0h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis.<\/jats:p>","DOI":"10.3389\/fimmu.2022.900906","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T09:49:32Z","timestamp":1655200172000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis"],"prefix":"10.3389","volume":"13","author":[{"given":"Shireen","family":"Mohammad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline E.","family":"O\u2019Riordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Verra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aimaretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Ferreira","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Dreisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Even\u00e4s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Gena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Tesse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"R\u00fctzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Collino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Calamita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Thiemermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.12688\/F1000RESEARCH.15758.1","article-title":"Recent Advances in Understanding and Managing Sepsis [version 1; peer review: 3 approved]","volume":"7","author":"Berg","year":"2018","journal-title":"F1000Research"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1172\/jci200215851","article-title":"Aquaporin Water Channels: Atomic Structure Molecular Dynamics Meet Clinical Medicine","volume":"109","author":"Kozono","year":"2002","journal-title":"J Clin Invest"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-018-0211-9","article-title":"Function of Aquaporins in Sepsis: A Systematic Review","volume":"8","author":"Rump","year":"2018","journal-title":"Cell Biosci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/boc.201100061","article-title":"Biophysical Assessment of Aquaporin-9 as Principal Facilitative Pathway in Mouse Liver Import of Glucogenetic Glycerol","volume":"104","author":"Calamita","year":"2012","journal-title":"Biol Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.297002","article-title":"Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice","volume":"286","author":"Jelen","year":"2011","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02355","article-title":"Aquaporin 9 Contributes to the Maturation Process and Inflammatory Cytokine Secretion of Murine Dendritic Cells","volume":"9","author":"de Santis","year":"2018","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/srep15319","article-title":"Aquaporin-9-Expressing Neutrophils Are Required for the Establishment of Contact Hypersensitivity","volume":"5","author":"Moniaga","year":"2015","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.71.2.212","article-title":"Neutrophil Leukocyte Motility Requires Directed Water Influx","volume":"71","author":"Loitto","year":"2022","journal-title":"J Leukoc Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000218","article-title":"Enhanced Expression of Aquaporin 9 in Activated Polymorphonuclear Leukocytes in Patients With Systemic Inflammatory Response Syndrome","volume":"42","author":"Matsushima","year":"2014","journal-title":"Shock"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.01.153","article-title":"Aquaporin-9 Facilitates Membrane Transport of Hydrogen Peroxide in Mammalian Cells","volume":"471","author":"Watanabe","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.006083","article-title":"Identification and Characterization of Potent and Selective Aquaporin-3 and Aquaporin-7 Inhibitors","volume":"294","author":"Sonntag","year":"2019","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.38.24737","article-title":"Molecular Characterization of a Broad Selectivity Neutral Solute Channel","volume":"273","author":"Tsukaguchi","year":"1998","journal-title":"J Biol Chem"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.00971-15","article-title":"Aquaporin-3 Controls Breast Cancer Cell Migration by Regulating Hydrogen Peroxide Transport and Its Downstream Cell Signaling","volume":"36","author":"Satooka","year":"2016","journal-title":"Mol Cell Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112398","article-title":"Chemokine-Dependent T Cell Migration Requires Aquaporin-3-Mediated Hydrogen Peroxide Uptake","volume":"209","author":"Hara-Chikuma","year":"2012","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.02.010","article-title":"Involvement of Aquaporin-3 in Epidermal Growth Factor Receptor Signaling via Hydrogen Peroxide Transport in Cancer Cells","volume":"471","author":"Hara-Chikuma","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8454","article-title":"Aquaporin-3-Mediated Hydrogen Peroxide Transport Is Required for NF-\u00ce\u00b0 B Signalling in Keratinocytes and Development of Psoriasis","volume":"6","author":"Hara-Chikuma","year":"2015","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.2ab0116-045r","article-title":"AQP8 Transports NOX2-Generated H 2 O 2 Across the Plasma Membrane to Promote Signaling in B Cells","volume":"100","author":"Bertolotti","year":"2016","journal-title":"J Leukocyte Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/cells10020435","article-title":"Ablation of Aquaporin-9 Ameliorates the Systemic Inflammatory Response of LPS-Induced Endotoxic Shock in Mouse","volume":"10","author":"Tesse","year":"2021","journal-title":"Cells"},{"key":"B19","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1074\/jbc.M110.139048","article-title":"Sodium Overload and Water Influx Activate the NALP3 Inflammasome","volume":"286","author":"Schorn","year":"2011","journal-title":"J Biol Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.534594","article-title":"Critical Role of Aquaporins in Interleukin 1\u03b2 (IL-1\u03b2)-Induced Inflammation","volume":"289","author":"Rabolli","year":"2014","journal-title":"J Biol Chem"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms22041845","article-title":"Aquaporins in Immune Cells and Inflammation: New Targets for Drug Development","volume":"22","author":"V da Silva","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.845237","article-title":"Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases","volume":"9","author":"Pimp\u00e3o","year":"2022","journal-title":"Front Mol Biosci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4226","article-title":"Aquaporins: Important But Elusive Drug Targets","volume":"13","author":"Verkman","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"B24","volume-title":"Compounds for Modulating Aquaporins","author":"Evenas","year":"2019"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1021\/cb300625g","article-title":"HyPer-3: A Genetically Encoded H2O2 Probe With Improved Performance for Ratiometric and Fluorescence Lifetime Imaging","volume":"8","author":"Bilan","year":"2013","journal-title":"ACS Chem Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.701275","article-title":"A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice","volume":"12","author":"Mohammad","year":"2021","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2019.158586","article-title":"Aquaporin-9 Is Involved in the Lipid-Lowering Activity of the Nutraceutical Silybin on Hepatocytes Through Modulation of Autophagy and Lipid Droplets Composition","volume":"1865","author":"Baldini","year":"2020","journal-title":"Biochim Biophys Acta - Mol Cell Biol Lipids"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.08.2162","article-title":"Ejection Fraction Pros and Cons: JACC State-Of-the-Art Review","volume":"72","author":"Marwick","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"14","DOI":"10.4103\/0972-5229.63031","article-title":"Sepsis-Induced Acute Kidney Injury","volume":"14","author":"Majumdar","year":"2010","journal-title":"Indian J Crit Care Med"},{"key":"B30","first-page":"64","article-title":"Biomarkers, Diagnosis and Management of Sepsis-Induced Acute Kidney Injury: A Narrative Review","volume":"7","author":"Zhang","year":"2015","journal-title":"Heart Lung Vessel"},{"key":"B31","doi-asserted-by":"publisher","first-page":"873S","DOI":"10.1378\/chest.126.4_meetingabstracts.873s","article-title":"Prognostic Significance of Elevated Serum Lactate Dehydrogenase (LDH) in Patients With Severe Sepsis","volume":"126","author":"Zein","year":"2004","journal-title":"Chest"},{"key":"B32","doi-asserted-by":"crossref","unstructured":"AbrahamE\n          Nuclear Factor-kB and Its Role in Sepsis-Associated Organ Failure2003","DOI":"10.1086\/374750"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.012435","article-title":"Inhibition of I\u03bab Kinase Reduces the Multiple Organ Dysfunction Caused by Sepsis in the Mouse","volume":"6","author":"Coldewey","year":"2013","journal-title":"DMM Dis Models Mech"},{"key":"B34","doi-asserted-by":"publisher","first-page":"477","DOI":"10.2147\/JIR.S178084","article-title":"Inflammasomes: Pandora\u2019s Box for Sepsis","volume":"11","author":"Kumar","year":"2018","journal-title":"J Inflammation Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.niox.2018.09.005","article-title":"Sulfur Dioxide Attenuates Sepsis-Induced Cardiac Dysfunction via Inhibition of NLRP3 Inflammasome Activation in Rats","volume":"81","author":"Yang","year":"2018","journal-title":"Nitric Oxide - Biol Chem"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/5219056","article-title":"Lung Neutrophilia in Myeloperoxidase Deficient Mice During the Course of Acute Pulmonary Inflammation","volume":"2016","author":"Kremserova","year":"2016","journal-title":"Oxid Med Cell Longevity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/135625","article-title":"Myeloperoxidase: A New Biomarker of Inflammation in Ischemic Heart Disease and Acute Coronary Syndromes","volume":"2008","author":"Loria","year":"2008","journal-title":"Mediators Inflamm"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-018-0029-2","article-title":"B-1a Cells Protect Mice From Sepsis-Induced Acute Lung Injury","volume":"24","author":"Aziz","year":"2018","journal-title":"Mol Med"}],"updated-by":[{"DOI":"10.3389\/fimmu.2025.1672460","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.900906\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T10:35:56Z","timestamp":1755772556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.900906\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,14]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2022.900906"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.900906","relation":{"correction":[{"id-type":"doi","id":"10.3389\/fimmu.2025.1672460","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,14]]},"article-number":"900906"}}