{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:32:31Z","timestamp":1787167951559,"version":"build-2736575974"},"reference-count":47,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Excessive inflammatory responses represent one of the primary causes of sepsis- associated acute kidney injury (S-AKI). The activation of the nuclear factor-kappa B (NF-\u03baB) signaling pathway plays a critical role in the pathogenesis and progression of S-AKI. Previous studies have demonstrated that ribosomal protein S3 (RPS3) serves as a pivotal regulator of the \nNF-\u03baB pathway; however, its specific biological functions in the context of S-AKI remain to be fully elucidated. This study aims to elucidate the regulatory mechanisms of RPS3 in S-AKI-associated inflammation and to explore the underlying molecular pathways. First, we conducted an analysis of RPS3 level in urine and \nTNF-\u03b1 level in serum from S-AKI patients recruited at our hospital. Second, we established a murine model of S-AKI by intraperitoneal injection of LPS, followed by the evaluation of renal function, inflammatory response, RPS3 expression, and \nNF-\u03baB activation in renal tissues. Finally, we explored the regulatory role and underlying mechanism of RPS3 in the \nLPS-induced inflammatory response in HK-2 cells through RPS3 knockdown and the introduction of an NF-\u03baB agonist. The results demonstrated that urinary RPS3 and serum TNF-\u03b1 levels were significantly elevated in patients with S-AKI, with a positive correlation observed between these two parameters. In \nLPS-induced S-AKI mice, renal function was impaired, accompanied by a robust inflammatory response, increased RPS3 protein expression, and enhanced NF-\u03baB activation in kidney tissue. Knockdown of RPS3 in HK-2 cells mitigated LPS-induced the inflammatory response and suppressed NF-\u03baB activation. However, the effects of RPS3 silencing were partially reversed upon intervention with an NF-\u03baB agonist. Collectively, these findings indicate that RPS3 plays a critical role in the inflammatory response of S-AKI via activation of the NF \u03baB signaling pathway, suggesting its potential as a novel therapeutic target for S-AKI.<\/jats:p>","DOI":"10.33549\/physiolres.935642","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T10:49:59Z","timestamp":1773226199000},"page":"63","source":"Crossref","is-referenced-by-count":1,"title":["RPS3 Aggravates Sepsis-Induced Acute Kidney Injury Through Activating NF-\u03baB Mediated Renal Inflammatory Responses"],"prefix":"10.33549","author":[{"given":"X","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"1.\tFleischmann-Struzek C, Mellhammar L, Rose N, Cassini A, Rudd KE, Schlattmann P, Allegranzi B, Reinhart K. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med 2020;46:1552-1562. https:\/\/doi.org\/10.1007\/s00134-020-06151-x","DOI":"10.1007\/s00134-020-06151-x"},{"key":"ref1","doi-asserted-by":"crossref","unstructured":"2.\tCarsetti A, Vitali E, Pesaresi L, Antolini R, Casarotta E, Damiani E, Adrario E, Donati A. Anesthetic management of patients with sepsis\/septic shock. Front Med (Lausanne) 2023;10:1150124. https:\/\/doi.org\/10.3389\/fmed.2023.1150124","DOI":"10.3389\/fmed.2023.1150124"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"3.\tRudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020;395:200-211. https:\/\/doi.org\/10.1016\/S0140-6736(19)32989-7","DOI":"10.1016\/S0140-6736(19)32989-7"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"4.\tTakeuchi T, Flannery AH, Liu LJ, Ghazi L, Cama-Olivares A, Fushimi K, Chen J, et al. Epidemiology of sepsis-associated acute kidney injury in the ICU with contemporary consensus definitions. Crit Care 2025;29:128. https:\/\/doi.org\/10.1186\/s13054-025-05351-5","DOI":"10.1186\/s13054-025-05351-5"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"5.\tFani F, Regolisti G, Delsante M, Cantaluppi V, Castellano G, Gesualdo L, Villa G, Fiaccadori E. Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J Nephrol 2018;31:351-359. https:\/\/doi.org\/10.1007\/s40620-017-0452-4","DOI":"10.1007\/s40620-017-0452-4"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"6.\tRicci Z, Polito A, Polito A, Ronco C. The implications and management of septic acute kidney injury. Nat Rev Nephrol 2011;7:218-225. https:\/\/doi.org\/10.1038\/nrneph.2011.15","DOI":"10.1038\/nrneph.2011.15"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"7.\tBellomo R, Kellum JA, Ronco C, Wald R, Martensson J, Maiden M, Bagshaw SM, et al. Acute kidney injury in sepsis. Intensive Care Med 2017;43:816-828. https:\/\/doi.org\/10.1007\/s00134-017-4755-7","DOI":"10.1007\/s00134-017-4755-7"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"8.\tPeerapornratana S, Manrique-Caballero CL, G\u00f3mez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 2019;96:1083-1099. https:\/\/doi.org\/10.1016\/j.kint.2019.05.026","DOI":"10.1016\/j.kint.2019.05.026"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"9.\tDev A, Iyer S, Razani B, Cheng G. NF-\u03baB and innate immunity. Curr Top Microbiol Immunol 2011;349:115-143. https:\/\/doi.org\/10.1007\/82_2010_102","DOI":"10.1007\/82_2010_102"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"10.\tNapetschnig J, Wu H. Molecular basis of NF-\u03baB signaling. Annu Rev Biophys 2013;42:443-468. https:\/\/doi.org\/10.1146\/annurev-biophys-083012-130338","DOI":"10.1146\/annurev-biophys-083012-130338"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"11.\tLiu Z, Yang D, Gao J, Xiang X, Hu X, Li S, Wu W, et al. Discovery and validation of miR-452 as an effective biomarker for acute kidney injury in sepsis. Theranostics 2020;10:11963-11975. https:\/\/doi.org\/10.7150\/thno.50093","DOI":"10.7150\/thno.50093"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"12.\tThair S, Russell JA. Noncanonical nuclear factor kappa B (NF-\u03baB) signaling and potential for therapeutics in sepsis. Curr Infect Dis Rep 2013;15:364-371. https:\/\/doi.org\/10.1007\/s11908-013-0362-0","DOI":"10.1007\/s11908-013-0362-0"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"13.\tGao X, Hardwidge PR. Ribosomal protein s3: a multifunctional target of attaching\/effacing bacterial pathogens. Front Microbiol 2011;2:137. https:\/\/doi.org\/10.3389\/fmicb.2011.00137","DOI":"10.3389\/fmicb.2011.00137"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"14.\tZhou D, Chen L, Wang Y, Gan L, Yuan M, Zhang L, Chen F. RNA binding protein RPS3 mediates microglial polarization by activating NLRP3 inflammasome via SIRT1 in ischemic stroke. J Stroke Cerebrovasc Dis 2023;32:107132. https:\/\/doi.org\/10.1016\/j.jstrokecerebrovasdis.2023.107132","DOI":"10.1016\/j.jstrokecerebrovasdis.2023.107132"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"15.\tYang L, Wang L, Tang Q, Liu Y, Meng C, Sun S, Chong Y, et al. Hsa_circ_0093884 bound to RNA-binding protein RPS3 ameliorates hepatocyte inflammation in anti-tuberculosis drug-induced liver injury by competitively activating SIRT1. Int Immunopharmacol 2022;110:109018. https:\/\/doi.org\/10.1016\/j.intimp.2022.109018","DOI":"10.1016\/j.intimp.2022.109018"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"16.\tP\u00e9rez-Hern\u00e1ndez EG, Delgado-Coello B, Luna-Reyes I, Mas-Oliva J. New insights into lipopolysaccharide inactivation mechanisms in sepsis. Biomed Pharmacother 2021;141:111890. https:\/\/doi.org\/10.1016\/j.biopha.2021.111890","DOI":"10.1016\/j.biopha.2021.111890"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"17.\tWang Y, Du P, Jiang D. Rigosertib inhibits MEK1-ERK pathway and alleviates lipopolysaccharide-induced sepsis. Immun Inflamm Dis 2021;9:991-999. https:\/\/doi.org\/10.1002\/iid3.458","DOI":"10.1002\/iid3.458"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"18.\tStasi A, Intini A, Divella C, Franzin R, Montemurno E, Grandaliano G, Ronco C, et al. Emerging role of lipopolysaccharide binding protein in sepsis-induced acute kidney injury. Nephrol Dial Transplant 2017;32:24-31. https:\/\/doi.org\/10.1093\/ndt\/gfw250","DOI":"10.1093\/ndt\/gfw250"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"19.\tLee HY, Park JH, Lee CH, Yan B, Ahn JH, Lee YJ, Park CW, et al. Changes of ribosomal protein S3 immunoreactivity and its new expression in microglia in the mice hippocampus after lipopolysaccharide treatment. Cell Mol Neurobiol 2012;32:577-586. https:\/\/doi.org\/10.1007\/s10571-012-9802-x","DOI":"10.1007\/s10571-012-9802-x"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"20.\tWan F, Weaver A, Gao X, Bern M, Hardwidge PR, Lenardo MJ. IKK\u03b2 phosphorylation regulates RPS3 nuclear translocation and NF-\u03baB function during infection with Escherichia coli strain O157:H7. Nat Immunol 2011;12:335-343. https:\/\/doi.org\/10.1038\/ni.2007","DOI":"10.1038\/ni.2007"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"21.\tDong J, Liao W, Peh HY, Tan WSD, Zhou S, Wong WSF. Ribosomal protein S3 gene silencing protects against cigarette smoke-induced acute lung injury. Mol Ther Nucleic Acids 2018;12:370-380. https:\/\/doi.org\/10.1016\/j.omtn.2018.05.027","DOI":"10.1016\/j.omtn.2018.05.027"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"22.\tSun J, Niu L, Wang Y, Zhao G, Tang L, Jiang J, Pan S, Ge X. MicroRNA\u201117\u20115p alleviates sepsis\u2011related acute kidney injury in mice by modulating inflammation and apoptosis. Mol Med Rep 2024;30:139. https:\/\/doi.org\/10.3892\/mmr.2024.13263","DOI":"10.3892\/mmr.2024.13263"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"23.\tWei J, Chen L, Wang D, Tang L, Xie Z, Chen W, Zhang S, Weng G. Upregulation of RIP3 promotes necroptosis via a ROS\u2011dependent NF\u2011\u03baB pathway to induce chronic inflammation in HK\u20112 cells. Mol Med Rep 2021;24:783. https:\/\/doi.org\/10.3892\/mmr.2021.12423","DOI":"10.3892\/mmr.2021.12423"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"24.\tTang C, Han H, Yan M, Zhu S, Liu J, Liu Z, He L, et al. PINK1-PRKN\/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 2018;14:880-897. https:\/\/doi.org\/10.1080\/15548627.2017.1405880","DOI":"10.1080\/15548627.2017.1405880"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"25.\tHuang Z, Zhang Y, Li H, Zhou Y, Zhang Q, Chen R, Jin T, et al. Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-\u03baB pathway activation through RPS3. Cell Death Dis 2019;10:936. https:\/\/doi.org\/10.1038\/s41419-019-2177-x","DOI":"10.1038\/s41419-019-2177-x"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"26.\tManrique-Caballero CL, Del Rio-Pertuz G, Gomez H. Sepsis-associated acute kidney injury. Crit Care Clin 2021;37:279-301. https:\/\/doi.org\/10.1016\/j.ccc.2020.11.010","DOI":"10.1016\/j.ccc.2020.11.010"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"27.\tWei W, Zhao Y, Zhang Y, Shou S, Jin H. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury. Open Life Sci 2023;18:20220700. https:\/\/doi.org\/10.1515\/biol-2022-0700","DOI":"10.1515\/biol-2022-0700"},{"key":"ref27","unstructured":"28.\tRag\u00e1n D, Horv\u00e1th-Szalai Z, Szirmay B, M\u00fchl D. Novel damage biomarkers of sepsis-related acute kidney injury. EJIFCC 2022;33:11-22."},{"key":"ref28","unstructured":"29.\tZhang Z. Biomarkers, diagnosis and management of sepsis-induced acute kidney injury: a narrative review. Heart Lung Vessel 2015;7:64-73."},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"30.\tMarcello M, Virz\u00ec GM, Muci\u00f1o-Bermejo MJ, Milan Manani S, Giavarina D, Salvador L, Ronco C, Zanella M. Subclinical AKI and clinical outcomes in elderly patients undergoing cardiac surgery: diagnostic utility of NGAL versus standard creatinine increase criteria. Cardiorenal Med 2022;12:94-105. https:\/\/doi.org\/10.1159\/000525221","DOI":"10.1159\/000525221"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"31.\tGeng J, Qiu Y, Qin Z, Su B. The value of kidney injury molecule 1 in predicting acute kidney injury in adult patients: a systematic review and Bayesian meta-analysis. J Transl Med 2021;19:105. https:\/\/doi.org\/10.1186\/s12967-021-02776-8","DOI":"10.1186\/s12967-021-02776-8"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"32.\tAl-Amodi HS, Abdelsattar S, Kasemy ZA, Bedair HM, Elbarbary HS, Kamel HFM. Potential Value of TNF-\u03b1 (-376 G\/A) polymorphism and Cystatin C (CysC) in the diagnosis of sepsis associated acute kidney injury (S-AKI) and prediction of mortality in critically Ill patients. Front Mol Biosci 2021;8:751299. https:\/\/doi.org\/10.3389\/fmolb.2021.751299","DOI":"10.3389\/fmolb.2021.751299"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"33.\tChiang TH, Yo C-H, Lee GH, Mathew A, Sugaya T, Li W-Y, Lee C-C. Accuracy of liver-type fatty acid-binding protein in predicting acute kidney injury: a meta-analysis. J Appl Lab Med 2022;7:421-436. https:\/\/doi.org\/10.1093\/jalm\/jfab092","DOI":"10.1093\/jalm\/jfab092"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"34.\tChousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 2017;39:517-528. https:\/\/doi.org\/10.1007\/s00281-017-0639-8","DOI":"10.1007\/s00281-017-0639-8"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"35.\tSchult L, Halbgebauer R, Karasu E, Huber-Lang M. Glomerular injury after trauma, burn, and sepsis. J Nephrol 2023;36:2417-2429. https:\/\/doi.org\/10.1007\/s40620-023-01718-5","DOI":"10.1007\/s40620-023-01718-5"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"36.\tPais T, Jorge S, Lopes JA. Acute kidney injury in sepsis. Int J Mol Sci 2024;25:5924. https:\/\/doi.org\/10.3390\/ijms25115924","DOI":"10.3390\/ijms25115924"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"37.\tLee S-Y, Lee Y-S, Choi H-M, Ko Y-S, Lee H-Y, Jo S-K, Cho W-W, Kim H-K. Distinct pathophysiologic mechanisms of septic acute kidney injury: role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury. Crit Care Med 2012;40:2997-3006. https:\/\/doi.org\/10.1097\/CCM.0b013e31825b912d","DOI":"10.1097\/CCM.0b013e31825b912d"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"38.\tLi Y-Y, Zhang G-Y, He J-P, Zhang D-D, Kong X-X, Yuan H-M, Chen F-L. Ufm1 inhibits LPS-induced endothelial cell inflammatory responses through the NF-\u03baB signaling pathway. Int J Mol Med 2017;39:1119-1126. https:\/\/doi.org\/10.3892\/ijmm.2017.2947","DOI":"10.3892\/ijmm.2017.2947"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"39.\tO'Dea E, Hoffmann A. NF-\u03baB signaling. Wiley Interdiscip Rev Syst Biol Med 2009;1:107-115. https:\/\/doi.org\/10.1002\/wsbm.30","DOI":"10.1002\/wsbm.30"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"40.\tHuang W, Li X, Wang D, Sun Y, Wang Q, Bu Y, Niu F. Curcumin reduces LPS-induced septic acute kidney injury through suppression of lncRNA PVT1 in mice. Life Sci 2020;254:117340. https:\/\/doi.org\/10.1016\/j.lfs.2020.117340","DOI":"10.1016\/j.lfs.2020.117340"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"41.\tXu L, Cao H, Xu P, Nie M, Zhao C. Circ_0114427 promotes LPS-induced septic acute kidney injury by modulating miR-495-3p\/TRAF6 through the NF-\u03baB pathway. Autoimmunity 2022;55:52-64. https:\/\/doi.org\/10.1080\/08916934.2021.1995861","DOI":"10.1080\/08916934.2021.1995861"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"42.\tWang P, Feng Z, Sang X, Chen W, Zhang X, Xiao J, Chen Y, et al. Kombucha ameliorates LPS-induced sepsis in a mouse model. Food Funct 2021;12:10263-10280. https:\/\/doi.org\/10.1039\/D1FO01839F","DOI":"10.1039\/D1FO01839F"},{"key":"ref42","doi-asserted-by":"crossref","unstructured":"43.\tLi H, Zhang X, Wang P, Zhou X, Liang H, Li C. Knockdown of circ-FANCA alleviates LPS-induced HK2 cell injury via targeting miR-93-5p\/OXSR1 axis in septic acute kidney injury. Diabetol Metab Syndr 2021;13:7. https:\/\/doi.org\/10.1186\/s13098-021-00625-8","DOI":"10.1186\/s13098-021-00625-8"},{"key":"ref43","doi-asserted-by":"crossref","unstructured":"44.\tJiang Z, Yang G, Wang G, Wan J, Zhang Y, Song W, Zhang H, et al. SEC14L3 knockdown inhibited clear cell renal cell carcinoma proliferation, metastasis and sunitinib resistance through an SEC14L3\/RPS3\/NF\u03baB positive feedback loop. J Exp Clin Cancer Res 2024;43:288. https:\/\/doi.org\/10.1186\/s13046-024-03206-5","DOI":"10.1186\/s13046-024-03206-5"},{"key":"ref44","doi-asserted-by":"crossref","unstructured":"45.\tStanborough T, Niederhauser J, Koch B, Bergler H, Pertschy B. Ribosomal protein S3 interacts with the NF-\u03baB inhibitor I\u03baB\u03b1. FEBS Lett 2014;588:659-664. https:\/\/doi.org\/10.1016\/j.febslet.2013.12.034","DOI":"10.1016\/j.febslet.2013.12.034"},{"key":"ref45","doi-asserted-by":"crossref","unstructured":"46.\tHodgson A, Wier EM, Fu K, Sun X, Yu H, Zheng W, Sham HP, et al. Metalloprotease NleC suppresses host NF-\u03baB\/inflammatory responses by cleaving p65 and interfering with the p65\/RPS3 interaction. PLoS Pathog 2015;11:e1004705. https:\/\/doi.org\/10.1371\/journal.ppat.1004705","DOI":"10.1371\/journal.ppat.1004705"},{"key":"ref46","doi-asserted-by":"crossref","unstructured":"47.\tChen G, Gao X, Jia X, Wang Y, Xu L, Yu D, Chang S, et al. Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma. Haematologica 2024;109:1206-1219. https:\/\/doi.org\/10.3324\/haematol.2023.282789","DOI":"10.3324\/haematol.2023.282789"}],"container-title":["Physiological Research"],"original-title":[],"deposited":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T10:50:12Z","timestamp":1773226212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2026\/75_63.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":47,"URL":"https:\/\/doi.org\/10.33549\/physiolres.935642","relation":{},"ISSN":["0862-8408","1802-9973"],"issn-type":[{"value":"0862-8408","type":"print"},{"value":"1802-9973","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,10]]}}}