{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:21:23Z","timestamp":1789042883789,"version":"build-2803163510"},"reference-count":50,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82270758"],"award-info":[{"award-number":["82270758"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82570862"],"award-info":[{"award-number":["82570862"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>Persistent inflammation is recognized as a major driver of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet upstream macrophage-activation signals remain incompletely understood. Here, we investigated whether the urokinase receptor (uPAR), traditionally linked to matrix remodeling, functions instead as an inflammatory signaling hub that links kidney injury to chronic fibrotic remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>In a unilateral renal ischemia\u2013reperfusion injury model, uPAR was induced during the fibrotic phase of postischemic kidney injury. Functional enhancement- and loss-of-function approaches revealed a striking dichotomy: exogenous urokinase (uPA) aggravated renal dysfunction, inflammation, oxidative stress, and fibrosis, whereas uPAR deletion was protective. Mechanistically, uPA\/uPAR signaling amplified macrophage inflammatory responses, enhancing M1 polarization, pro-inflammatory cytokine production, reactive oxygen species generation, and NF-\u03baB activation. Molecular docking, mutational modeling, and co-immunoprecipitation analyses revealed a previously underappreciated association between activated uPAR and toll-like receptor 4 (TLR4)-containing complexes. This interaction enhanced myeloid differentiation primary response gene 88-dependent NF-\u03baB signaling and potentiated macrophage inflammatory amplification rather than initiating inflammation independently. NF-\u03baB blockade abolished the pro-inflammatory effects of uPA\/uPAR signaling, establishing the functional importance of this pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>We demonstrate that uPA-activated uPAR engages TLR4-associated signaling to intensify macrophage-driven inflammation, oxidative stress, and fibrotic remodeling. These findings redefine uPAR as a molecular switch governing maladaptive kidney repair and identify the uPA\/uPAR\u2013TLR4 signaling interface as a promising therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that the uPA\/uPAR\u2013TLR4 axis is involved in regulating the progression from AKI to fibrosis. Targeting this signaling node may represent a novel strategy to interrupt maladaptive repair and prevent CKD following AKI.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      00, 000\u2013000.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15230864261486342","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T16:00:30Z","timestamp":1788796830000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["uPAR Amplifies Macrophage Inflammation\n                    <i>via<\/i>\n                    NF-\u03baB Pathway to Promote Fibrotic Transition Following Acute Kidney Injury"],"prefix":"10.1177","author":[{"given":"Shengchun","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."},{"name":"Chinese PLA Medical School, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."},{"name":"Chinese PLA Medical School, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaona","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."},{"name":"Chinese PLA Medical School, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."},{"name":"Chinese PLA Medical School, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."},{"name":"Chinese PLA Medical School, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanda","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangmei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Chinese PLA General Hospital First Medical Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Nephrology, State Key Laboratory of Kidney Diseases, 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