{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:07:02Z","timestamp":1792649222314,"version":"4.5.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,8]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Lipocalin-2 upregulation paralleled intracellular uromodulin aggregates in mouse and cellular models of autosomal dominant tubulointerstitial kidney disease because of pathogenic uromodulin.<\/jats:p>\n <\/jats:list-item>\n \n The induction of lipocalin-2 was triggered by mutant uromodulin accumulation and endoplasmic reticulum stress in tubular cells.<\/jats:p>\n <\/jats:list-item>\n \n Genetic loss of lipocalin-2 reduced iron deposits in the kidney but did not affect kidney damage, indicating that lipocalin-2 was not driving disease progression.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Autosomal dominant tubulointerstitial kidney disease due to pathogenic\n UMOD<\/jats:italic>\n variants (ADTKD-\n UMOD<\/jats:italic>\n ) is a toxic proteinopathy caused by intracellular accumulation of mutant uromodulin (UMOD) and endoplasmic reticulum (ER) stress. Lipocalin-2 (LCN2) is an acute phase protein induced by ER stress with context-dependent roles in kidney injury.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To examine the role of LCN2 in ADTKD-\n UMOD<\/jats:italic>\n , we used\n Umod<\/jats:italic>\n knock-in mouse models (C171Y, R186S, C125R), urine samples from affected patients, and mIMCD3 cells expressing wild-type or mutant UMOD. LCN2 expression was assessed by immunoblotting, immunostaining, and ELISA. Autophagy was stimulated with Torin1 to evaluate effects on LCN2 induction.\n Umod<\/jats:italic>\n R186S\/+<\/jats:sup>\n mice were crossed with\n Lcn2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice to determine the impact of LCN2 deficiency on disease progression.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Robust LCN2 induction was observed in kidneys and urine of\n Umod<\/jats:italic>\n R186S\/+<\/jats:sup>\n ,\n Umod<\/jats:italic>\n C125R\/+<\/jats:sup>\n , and\n Umod<\/jats:italic>\n C171Y\/+<\/jats:sup>\n mice, correlating with UMOD aggregates and ER stress severity in thick ascending limb cells. In patients, specific\n UMOD<\/jats:italic>\n variants were associated with elevated urinary LCN2. In mIMCD3 cells expressing mutant UMOD (C170Y, R185S), treatment with Torin1 reduced aggregates and attenuated LCN2 induction. Genetic deletion of\n Lcn2<\/jats:italic>\n in\n Umod<\/jats:italic>\n R186S\/+<\/jats:sup>\n mice decreased interstitial iron deposition but did not alter UMOD accumulation, interstitial inflammation, or fibrosis.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n LCN2 was induced by intracellular UMOD aggregates and ER stress in various models of ADTKD-\n UMOD<\/jats:italic>\n . Although it influenced iron handling, LCN2 did not drive fibrosis or inflammation, supporting a role as a biomarker of toxic proteinopathy rather than a therapeutic target.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000001077","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T16:02:24Z","timestamp":1774540944000},"page":"1689-1703","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":3,"title":["Lipocalin-2 Is Induced by Uromodulin Aggregates without Affecting Kidney Disease Progression in Autosomal Dominant Tubulointerstitial Kidney Disease\u2013U MOD"],"prefix":"10.1681","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9617-7438","authenticated-orcid":false,"given":"Jennifer","family":"Lake","sequence":"first","affiliation":[{"name":"Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology, University of Zurich, Zurich, Switzerland"},{"name":"Universit\u00e9 de Paris Cit\u00e9, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8254-3505","authenticated-orcid":false,"given":"Marta","family":"Mariniello","sequence":"additional","affiliation":[{"name":"Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-7796","authenticated-orcid":false,"given":"Guglielmo","family":"Schiano","sequence":"additional","affiliation":[{"name":"Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Guo","sequence":"additional","affiliation":[{"name":"Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Mabillard","sequence":"additional","affiliation":[{"name":"Newcastle University, Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1881-3782","authenticated-orcid":false,"given":"John A.","family":"Sayer","sequence":"additional","affiliation":[{"name":"Newcastle University, Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom"},{"name":"Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom"},{"name":"Newcastle Biomedical Research Centre, Newcastle University, Newcastle, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1178-7980","authenticated-orcid":false,"given":"Eric","family":"Olinger","sequence":"additional","affiliation":[{"name":"Center for Human Genetics, Cliniques universitaires Saint-Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6107-8125","authenticated-orcid":false,"given":"Fabiola","family":"Terzi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris Cit\u00e9, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3744-4767","authenticated-orcid":false,"given":"Olivier","family":"Devuyst","sequence":"additional","affiliation":[{"name":"Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology, University of Zurich, Zurich, Switzerland"},{"name":"Institute for Rare 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