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However, the cellular initiators that connect early immune activation to tubular epithelial\u2013mesenchymal transition (EMT) during RIRI remain poorly defined. Here, we established a human RIRI model by modifying the surgical procedures in patients undergoing radical nephrectomy and confirmed successful injury induction by tubular dilation, severe mitochondrial swelling and increased apoptosis in renal tissues. Using single\u2010cell RNA sequencing, we uncovered an underappreciated dendritic cell (DC) subset, CD11c\n                    <jats:sup>+<\/jats:sup>\n                    AREG\n                    <jats:sup>+<\/jats:sup>\n                    DCs, that expands after RIRI, coinciding with EMT activation in tubular epithelial cells at early stages. Notably, ligand\u2013receptor inference revealed markedly enhanced communication between CD11c\n                    <jats:sup>+<\/jats:sup>\n                    AREG\n                    <jats:sup>+<\/jats:sup>\n                    DCs and tubular epithelial cells after RIRI, suggesting the AREG\u2013EGFR as a dominant axis. Mechanistically, CD11c\n                    <jats:sup>+<\/jats:sup>\n                    AREG\n                    <jats:sup>+<\/jats:sup>\n                    DCs initiate and promote tubular EMT via AREG\u2010dependent EGFR signalling, establishing a direct causal link between this DC population and injured tubular epithelial cells. Importantly, Areg knockdown or DC depletion significantly alleviated tubular damage and fibrosis and preserved kidney function in the IRI mouse model, which highlights these cells could be potential therapeutic targets for mitigating RIRI.\n                  <\/jats:p>","DOI":"10.1111\/cpr.70287","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:01:03Z","timestamp":1791241263000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting a Novel\n                    <scp>AREG<\/scp>\n                    <sup>+<\/sup>\n                    Dendritic Cell Alleviates Renal Fibrosis Induced by Ischemia\u2013Reperfusion Injury"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1924-6489","authenticated-orcid":false,"given":"Xin","family":"Luo","sequence":"first","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longbin","family":"Xiong","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3902-8089","authenticated-orcid":false,"given":"Lihao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5213-4655","authenticated-orcid":false,"given":"Yulu","family":"Peng","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangpeng","family":"Zou","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Huang","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yisong","family":"Lin","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanji","family":"Zhan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Division of Nephrology Nanfang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangjian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4740-805X","authenticated-orcid":false,"given":"Youhua","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Division of Nephrology Nanfang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-3777","authenticated-orcid":false,"given":"Chunping","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Urology, Minimally Invasive Surgery Center The First Affiliated Hospital of Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9357-9810","authenticated-orcid":false,"given":"Baokui","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"},{"name":"Department of Intensive Care Unit Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1821-4587","authenticated-orcid":false,"given":"Zhiling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Urology Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine  Guangzhou China"},{"name":"Guangdong Provincial Clinical Research Center for Cancer; State Key Laboratory of Oncology in Southern China  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"issue":"2","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.kint.2019.02.009","article-title":"Regulated Necrosis in Kidney Ischemia\u2010Reperfusion Injury","volume":"96","author":"Pefanis A.","year":"2019","journal-title":"Kidney International"},{"issue":"9","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41581-021-00418-2","article-title":"Postoperative Acute Kidney Injury in Adult Non\u2010Cardiac Surgery: Joint Consensus Report of the Acute Disease Quality Initiative and Perioperative Quality Initiative","volume":"17","author":"Prowle J. R.","year":"2021","journal-title":"Nature Reviews. Nephrology"},{"issue":"1","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1056\/NEJMra1214243","article-title":"Acute Kidney Injury and Chronic Kidney Disease as Interconnected Syndromes","volume":"371","author":"Chawla L. S.","year":"2014","journal-title":"New England Journal of Medicine"},{"issue":"1","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1186\/s13054-016-1353-y","article-title":"Acute Kidney Injury: Short\u2010Term and Long\u2010Term Effects","volume":"20","author":"Doyle J. F.","year":"2016","journal-title":"Critical Care"},{"issue":"2","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.23876\/j.krcp.2018.37.2.119","article-title":"Epidemiology of Continuous Renal Replacement Therapy in Korea: Results From the National Health Insurance Service Claims Database From 2005 to 2016","volume":"37","author":"Park S.","year":"2018","journal-title":"Kidney Research and Clinical Practice"},{"issue":"3","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.kint.2017.09.017","article-title":"Knockout of the Interleukin\u201036 Receptor Protects Against Renal Ischemia\u2010Reperfusion Injury by Reduction of Proinflammatory Cytokines","volume":"93","author":"Nishikawa H.","year":"2018","journal-title":"Kidney International"},{"issue":"4","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1681\/ASN.2019060601","article-title":"Granulocyte Colony\u2010Stimulating Factor Attenuates Renal Ischemia\u2010Reperfusion Injury by Inducing Myeloid\u2010Derived Suppressor Cells","volume":"31","author":"Yan J. J.","year":"2020","journal-title":"Journal of the American Society of Nephrology"},{"issue":"3","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1000245","article-title":"Can Animal Models of Disease Reliably Inform Human Studies?","volume":"7","author":"Worp H. B.","year":"2010","journal-title":"PLoS Medicine"},{"issue":"2","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1046\/j.1523-1755.2003.00100.x","article-title":"A Randomized, Placebo\u2010Controlled Trial of IGF\u20101 for Delayed Graft Function: A Human Model to Study Postischemic ARF","volume":"64","author":"Hladunewich M. A.","year":"2003","journal-title":"Kidney International"},{"issue":"4","key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1053\/ajkd.2000.17659","article-title":"Atrial Natriuretic Factor in Oliguric Acute Renal Failure. Anaritide Acute Renal Failure Study Group","volume":"36","author":"Lewis J.","year":"2000","journal-title":"American Journal of Kidney Diseases"},{"issue":"6","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1016\/j.juro.2015.01.093","article-title":"Decline in Renal Function After Partial Nephrectomy: Etiology and Prevention","volume":"193","author":"Mir M. C.","year":"2015","journal-title":"Journal of Urology"},{"issue":"5","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.eururo.2021.12.036","article-title":"What Happens to the Preserved Renal Parenchyma After Clamped Partial Nephrectomy?","volume":"81","author":"Xiong L.","year":"2022","journal-title":"European Urology"},{"issue":"9","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"107610","DOI":"10.1016\/j.isci.2023.107610","article-title":"Long\u2010Term Effect of Acute Ischemic Injury on the Kidney Underwent Clamped Partial Nephrectomy","volume":"26","author":"Zhou Z.","year":"2023","journal-title":"iScience"},{"issue":"2","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1097\/JS9.0000000000000938","article-title":"Longitudinal Changes in Renal Parenchymal Volume and Function Status After Partial Nephrectomy: A Retrospective Cohort Study","volume":"110","author":"Xiong L.","year":"2024","journal-title":"International Journal of Surgery"},{"issue":"3","key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1681\/ASN.2012080786","article-title":"Tolerance of the Human Kidney to Isolated Controlled Ischemia","volume":"24","author":"Parekh D. J.","year":"2013","journal-title":"Journal of the American Society of Nephrology"},{"issue":"1","key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1186\/s12882-020-02025-y","article-title":"RNA\u2010Seq Identifies Condition\u2010Specific Biological Signatures of Ischemia\u2010Reperfusion Injury in the Human Kidney","volume":"21","author":"Park M.","year":"2020","journal-title":"BMC Nephrology"},{"issue":"7","key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/sj.ki.5002132","article-title":"Resident Dendritic Cells Are the Predominant TNF\u2010Secreting Cell in Early Renal Ischemia\u2010Reperfusion Injury","volume":"71","author":"Dong X.","year":"2007","journal-title":"Kidney International"},{"issue":"3","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1681\/ASN.2007060684","article-title":"Renal Dendritic Cells Stimulate IL\u201010 Production and Attenuate Nephrotoxic Nephritis","volume":"19","author":"Scholz J.","year":"2008","journal-title":"Journal of the American Society of Nephrology"},{"issue":"6","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.cytogfr.2005.04.008","article-title":"Dendritic Cell Trafficking: More Than Just Chemokines","volume":"16","author":"Sozzani S.","year":"2005","journal-title":"Cytokine & Growth Factor Reviews"},{"issue":"12","key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.it.2004.10.007","article-title":"A Central Role for Tissue\u2010Resident Dendritic Cells in Innate Responses","volume":"25","author":"Foti M.","year":"2004","journal-title":"Trends in Immunology"},{"issue":"2","key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1084\/jem.20050810","article-title":"Dendritic Cell Maturation by Innate Lymphocytes: Coordinated Stimulation of Innate and Adaptive Immunity","volume":"202","author":"Munz C.","year":"2005","journal-title":"Journal of Experimental Medicine"},{"key":"e_1_2_10_23_1","volume-title":"Urologic Surgery","author":"Hinman F.","year":"1989"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1146\/annurev-physiol-052521-121841","article-title":"How Many Cell Types Are in the Kidney and What Do They Do?","volume":"84","author":"Balzer M. S.","year":"2022","journal-title":"Annual Review of Physiology"},{"issue":"8","key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1681\/ASN.2018020125","article-title":"Single\u2010Cell Transcriptomics of a Human Kidney Allograft Biopsy Specimen Defines a Diverse Inflammatory Response","volume":"29","author":"Wu H.","year":"2018","journal-title":"Journal of the American Society of Nephrology"},{"issue":"12","key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1681\/ASN.2020010052","article-title":"Single\u2010Cell Profiling of AKI in a Murine Model Reveals Novel Transcriptional Signatures, Profibrotic Phenotype, and Epithelial\u2010To\u2010Stromal Crosstalk","volume":"31","author":"Rudman\u2010Melnick V.","year":"2020","journal-title":"Journal of the American Society of Nephrology"},{"issue":"1","key":"e_1_2_10_27_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41536-021-00156-w","article-title":"Defining the Variety of Cell Types in Developing and Adult Human Kidneys by Single\u2010Cell RNA Sequencing","volume":"6","author":"Schumacher A.","year":"2021","journal-title":"npj Regenerative Medicine"},{"issue":"1","key":"e_1_2_10_28_1","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.1038\/s41467-019-10861-2","article-title":"A Single\u2010Nucleus RNA\u2010Sequencing Pipeline to Decipher the Molecular Anatomy and Pathophysiology of Human Kidneys","volume":"10","author":"Lake B. B.","year":"2019","journal-title":"Nature Communications"},{"issue":"5","key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.kint.2022.02.023","article-title":"Kidney Repair and Regeneration: Perspectives of the NIDDK (Re)building a Kidney Consortium","volume":"101","author":"Naved B. A.","year":"2022","journal-title":"Kidney International"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1756-8722-1-9","article-title":"Ganoderma Lucidum Polysaccharides Can Induce Human Monocytic Leukemia Cells Into Dendritic Cells With Immuno\u2010Stimulatory Function","volume":"1","author":"Chan W. K.","year":"2008","journal-title":"Journal of Hematology & Oncology"},{"issue":"2","key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nrm3048","article-title":"Feedback Regulation of EGFR Signalling: Decision Making by Early and Delayed Loops","volume":"12","author":"Avraham R.","year":"2011","journal-title":"Nature Reviews. 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