{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:07:33Z","timestamp":1789002453801,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T00:00:00Z","timestamp":1693872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Uehara Memorial Foundation Overseas Research Fellowship","award":["#202360162"],"award-info":[{"award-number":["#202360162"]}]},{"name":"The Uehara Memorial Foundation Overseas Research Fellowship","award":["R01DK121200"],"award-info":[{"award-number":["R01DK121200"]}]},{"name":"The Uehara Memorial Foundation Overseas Research Fellowship","award":["I01BX005322"],"award-info":[{"award-number":["I01BX005322"]}]},{"name":"The Uehara Memorial Foundation Overseas Research Fellowship","award":["20CDA35320006"],"award-info":[{"award-number":["20CDA35320006"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship","award":["#202360162"],"award-info":[{"award-number":["#202360162"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship","award":["R01DK121200"],"award-info":[{"award-number":["R01DK121200"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship","award":["I01BX005322"],"award-info":[{"award-number":["I01BX005322"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship","award":["20CDA35320006"],"award-info":[{"award-number":["20CDA35320006"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney diseases","award":["#202360162"],"award-info":[{"award-number":["#202360162"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney diseases","award":["R01DK121200"],"award-info":[{"award-number":["R01DK121200"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney diseases","award":["I01BX005322"],"award-info":[{"award-number":["I01BX005322"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney diseases","award":["20CDA35320006"],"award-info":[{"award-number":["20CDA35320006"]}]},{"name":"Veterans Affairs","award":["#202360162"],"award-info":[{"award-number":["#202360162"]}]},{"name":"Veterans Affairs","award":["R01DK121200"],"award-info":[{"award-number":["R01DK121200"]}]},{"name":"Veterans Affairs","award":["I01BX005322"],"award-info":[{"award-number":["I01BX005322"]}]},{"name":"Veterans Affairs","award":["20CDA35320006"],"award-info":[{"award-number":["20CDA35320006"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["#202360162"],"award-info":[{"award-number":["#202360162"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["R01DK121200"],"award-info":[{"award-number":["R01DK121200"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["I01BX005322"],"award-info":[{"award-number":["I01BX005322"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20CDA35320006"],"award-info":[{"award-number":["20CDA35320006"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Society of Nephrology-KidneyCure","award":["#202360162"],"award-info":[{"award-number":["#202360162"]}]},{"name":"American Society of Nephrology-KidneyCure","award":["R01DK121200"],"award-info":[{"award-number":["R01DK121200"]}]},{"name":"American Society of Nephrology-KidneyCure","award":["I01BX005322"],"award-info":[{"award-number":["I01BX005322"]}]},{"name":"American Society of Nephrology-KidneyCure","award":["20CDA35320006"],"award-info":[{"award-number":["20CDA35320006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Elevated levels of circulating tumor necrosis factor receptors 1 and 2 (cTNFR1\/2) predict chronic kidney disease (CKD) progression; however, the mechanisms of their release remain unknown. Whether acute kidney injury (AKI) drives cTNFR1\/2 elevations and whether they predict disease outcomes after AKI remain unknown. In this study, we used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, and toxic), and progression to fibrosis, nephrectomy, and related single-cell RNA-sequencing datasets to experimentally test the role of kidney injury on cTNFR1\/2 levels. We show that TNFR1\/2 serum and urine levels are highly elevated in all of the mouse models of kidney injury tested, beginning within one hour post injury, and correlate with its severity. Consistent with this, serum and urine TNFR1\/2 levels are increased in AKI patients and correlate with the severity of kidney failure. Kidney tissue expression of TNFR1\/2 after AKI is only slightly increased and bilateral nephrectomies lead to strong cTNFR1\/2 elevations, suggesting the release of these receptors by extrarenal sources. The injection of the uremic toxin indoxyl sulfate in healthy mice induces moderate cTNFR1\/2 elevations. Moreover, TNF neutralization does not affect early cTNFR1\/2 elevations after AKI. These data suggest that cTNFR1\/2 levels in AKI do not reflect injury-induced TNF activity, but rather a rapid response to loss of kidney function and uremia. In contrast to traditional disease biomarkers, such as serum creatinine or BUN, cTNFR1\/2 levels remain elevated for weeks after severe kidney injury. At these later timepoints, cTNFR1\/2 levels positively correlate with remaining kidney injury. During the AKI-to-CKD transition, elevations of TNFR1\/2 kidney expression and of cTNFR2 levels correlate with kidney fibrosis levels. In conclusion, our data demonstrate that kidney injury drives acute increases in cTNFR1\/2 serum levels, which negatively correlate with kidney function. Sustained TNFR1\/2 elevations after kidney injury during AKI-to-CKD transition reflect persistent tissue injury and progression to kidney fibrosis.<\/jats:p>","DOI":"10.3390\/cells12182214","type":"journal-article","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T09:59:31Z","timestamp":1693907971000},"page":"2214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Acute Kidney Injury-Induced Circulating TNFR1\/2 Elevations Correlate with Persistent Kidney Injury and Progression to Fibrosis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-9920","authenticated-orcid":false,"given":"Akshayakeerthi","family":"Arthanarisami","sequence":"first","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Komaru","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charikleia","family":"Katsouridi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah K.","family":"Verges","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai M.","family":"Abdelmageed","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Herrlich","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"},{"name":"VA St. Louis Health Care System, John Cochran Division, St. Louis, MO 63106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Kefaloyianni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1681\/ASN.2011060627","article-title":"Circulating TNF Receptors 1 and 2 Predict ESRD in Type 2 Diabetes","volume":"23","author":"Niewczas","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1681\/ASN.2011060628","article-title":"Circulating TNF Receptors 1 and 2 Predict Stage 3 CKD in Type 1 Diabetes","volume":"23","author":"Gohda","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"730","DOI":"10.5551\/jat.21055","article-title":"Circulating TNF Receptor 2 Is Closely Associated with the Kidney Function in Non-Diabetic Japanese Subjects","volume":"21","author":"Kurashina","year":"2014","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lee, S.M., Yang, S., Cha, R., Kim, M., An, J.N., Paik, J.H., Kim, D.K., Kang, S.-W., Lim, C.S., and Kim, Y.S. (2014). Circulating TNF Receptors Are Significant Prognostic Biomarkers for Idiopathic Membranous Nephropathy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104354"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sonoda, Y., Gohda, T., Suzuki, Y., Omote, K., Ishizaka, M., Matsuoka, J., and Tomino, Y. (2015). Circulating TNF Receptors 1 and 2 Are Associated with the Severity of Renal Interstitial Fibrosis in IgA Nephropathy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122212"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Oh, Y.J., An, J.N., Kim, C.T., Yang, S.H., Lee, H., Kim, D.K., Joo, K.W., Paik, J.H., Kang, S.-W., and Park, J.T. (2015). Circulating Tumor Necrosis Factor \u03b1 Receptors Predict the Outcomes of Human IgA Nephropathy: A Prospective Cohort Study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132826"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/ki.2014.330","article-title":"Elevation of Circulating TNF Receptors 1 and 2 Increases the Risk of End-Stage Renal Disease in American Indians with Type 2 Diabetes","volume":"87","author":"Pavkov","year":"2015","journal-title":"Kidney Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1177\/0961203316631634","article-title":"Increased Concentration of Plasma TNFR1 and TNFR2 in Paediatric Lupus Nephritis","volume":"25","author":"Patel","year":"2016","journal-title":"Lupus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/s41591-019-0415-5","article-title":"A Signature of Circulating Inflammatory Proteins and Development of End-Stage Renal Disease in Diabetes","volume":"25","author":"Niewczas","year":"2019","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1681\/ASN.2019070723","article-title":"Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children","volume":"31","author":"Greenberg","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1681\/ASN.2021060735","article-title":"Longitudinal TNFR1 and TNFR2 and Kidney Outcomes: Results from AASK and VA NEPHRON-D","volume":"33","author":"Chen","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1053\/j.ajkd.2021.09.018","article-title":"Associations of Plasma Biomarkers of Inflammation, Fibrosis, and Kidney Tubular Injury With Progression of Diabetic Kidney Disease: A Cohort Study","volume":"79","author":"Shlipak","year":"2022","journal-title":"Am. J. Kidney Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"43520","DOI":"10.1038\/srep43520","article-title":"Circulating TNF Receptors 1 and 2 Predict Mortality in Patients with End-Stage Renal Disease Undergoing Dialysis","volume":"7","author":"Gohda","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e6666","DOI":"10.1097\/MD.0000000000006666","article-title":"Circulating TNF Receptors Predict Cardiovascular Disease in Patients with Chronic Kidney Disease","volume":"96","author":"Bae","year":"2017","journal-title":"Medicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.2337\/dc13-2580","article-title":"Association of Serum Concentration of TNFR1 with All-Cause Mortality in Patients with Type 2 Diabetes and Chronic Kidney Disease: Follow-up of the SURDIAGENE Cohort","volume":"37","author":"Saulnier","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1681\/ASN.2021111453","article-title":"Acute Kidney Injury Associates with Long-Term Increases in Plasma TNFR1, TNFR2, and KIM-1: Findings from the CRIC Study","volume":"33","author":"McCoy","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"155727","DOI":"10.1016\/j.cyto.2021.155727","article-title":"Soluble TNF Receptors Predict Acute Kidney Injury and Mortality in Critically Ill COVID-19 Patients: A Prospective Observational Study","volume":"149","author":"Ferrando","year":"2022","journal-title":"Cytokine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15350","DOI":"10.1038\/s41598-020-72003-9","article-title":"TNFR1, TNFR2, Neutrophil Gelatinase-Associated Lipocalin and Heparin Binding Protein in Identifying Sepsis and Predicting Outcome in an Intensive Care Cohort","volume":"10","author":"Bergquist","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.kint.2020.06.037","article-title":"Results from the TRIBE-AKI Study Found Associations between Post-Operative Blood Biomarkers and Risk of Chronic Kidney Disease after Cardiac Surgery","volume":"99","author":"Menez","year":"2021","journal-title":"Kidney Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1053\/j.ajkd.2022.08.007","article-title":"Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies","volume":"81","author":"Coca","year":"2023","journal-title":"Am. J. Kidney Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e167731","DOI":"10.1172\/jci.insight.167731","article-title":"Longitudinal Biomarkers and Kidney Disease Progression after Acute Kidney Injury","volume":"8","author":"Wen","year":"2023","journal-title":"JCI Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/sj.ki.5000021","article-title":"The Association of Serum Lipids and Inflammatory Biomarkers with Renal Function in Men with Type II Diabetes Mellitus","volume":"69","author":"Lin","year":"2006","journal-title":"Kidney Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s00125-009-1597-z","article-title":"Lipid and Inflammatory Biomarkers and Kidney Function Decline in Type 2 Diabetes","volume":"53","author":"Lin","year":"2009","journal-title":"Diabetologia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nm.2144","article-title":"Epithelial Cell Cycle Arrest in G2\/M Mediates Kidney Fibrosis after Injury","volume":"16","author":"Yang","year":"2010","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e87023","DOI":"10.1172\/jci.insight.87023","article-title":"ADAM17 Substrate Release in Proximal Tubule Drives Kidney Fibrosis","volume":"1","author":"Kefaloyianni","year":"2016","journal-title":"JCI Insight"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1681\/ASN.2019030321","article-title":"Proximal Tubule-Derived Amphiregulin Amplifies and Integrates Profibrotic EGF Receptor Signals in Kidney Fibrosis","volume":"30","author":"Kefaloyianni","year":"2019","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1681\/ASN.2014060543","article-title":"Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy","volume":"26","author":"Yang","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38869","DOI":"10.1074\/jbc.M110.166686","article-title":"Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-Regulation of E-Selectin","volume":"285","author":"Ito","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1093\/ndt\/gfac290","article-title":"TNF or EGFR Inhibition Equally Block AKI-to-CKD Transition: Opportunities for Etanercept Treatment","volume":"38","author":"Abdelmageed","year":"2023","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"eabm5900","DOI":"10.1126\/sciadv.abm5900","article-title":"Identification of Kidney Injury Released Circulating Osteopontin as Causal Agent of Respiratory Failure","volume":"8","author":"Khamissi","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.cmet.2022.05.010","article-title":"Mapping the Single-Cell Transcriptomic Response of Murine Diabetic Kidney Disease to Therapies","volume":"34","author":"Wu","year":"2022","journal-title":"Cell Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1681\/ASN.2013101062","article-title":"The Uremic Toxicity of Indoxyl Sulfate and P-Cresyl Sulfate: A Systematic Review","volume":"25","author":"Vanholder","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1038\/s41598-017-03130-z","article-title":"Indoxyl Sulfate (IS)-Mediated Immune Dysfunction Provokes Endothelial Damage in Patients with End-Stage Renal Disease (ESRD)","volume":"7","author":"Kim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e94716","DOI":"10.1172\/jci.insight.94716","article-title":"Molecular Characterization of the Transition from Acute to Chronic Kidney Injury Following Ischemia\/Reperfusion","volume":"2","author":"Liu","year":"2017","journal-title":"JCI Insight"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"F1098","DOI":"10.1152\/ajprenal.00199.2018","article-title":"Rodent Models of AKI-CKD Transition","volume":"315","author":"Fu","year":"2018","journal-title":"Am. J. Physiol.-Ren. Physiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/18\/2214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:46:59Z","timestamp":1760129219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/18\/2214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,5]]},"references-count":35,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cells12182214"],"URL":"https:\/\/doi.org\/10.3390\/cells12182214","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.04.03.534558","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,5]]}}}