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Lookup NU author(s): Dr Holly MabillardORCiD, Professor John SayerORCiD
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Copyright © 2026 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of NephrologyBackground: – Autosomal dominant tubulointerstitial kidney disease due to pathogenic UMOD variants (ADTKD-UMOD) is a toxic proteinopathy caused by intracellular accumulation of mutant uromodulin and endoplasmic reticulum (ER) stress. Lipocalin-2 (LCN2) is an acute-phase protein induced by ER stress with context-dependent roles in kidney injury.Methods: – To examine the role of LCN2 in ADTKD-UMOD, we used Umod knock-in mouse models (C171Y, R186S, C125R), urine samples from affected patients, and mIMCD3 cells expressing wild-type or mutant uromodulin. LCN2 expression was assessed by immunoblotting, immunostaining, and ELISA. Autophagy was stimulated with Torin1 to evaluate effects on LCN2 induction. UmodR186S/+ mice were crossed with Lcn2−/− mice to determine the impact of LCN2 deficiency on disease progression.Results: – Robust LCN2 induction was observed in kidneys and urine of UmodR186S/+, UmodC125R/+, and UmodC171Y/+ mice, correlating with uromodulin aggregates and ER stress severity in thick ascending limb cells. In patients, specific UMOD variants were associated with elevated urinary LCN2. In mIMCD3 cells expressing mutant uromodulin (C170Y, R185S), treatment with Torin1 reduced aggregates and attenuated LCN2 induction. Genetic deletion of Lcn2 in UmodR186S/+ mice decreased interstitial iron deposition but did not alter uromodulin accumulation, interstitial inflammation, or fibrosis.Conclusions: – LCN2 was induced by intracellular uromodulin aggregates and ER stress in various models of ADTKD-UMOD. 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.
Author(s): Lake J, Mariniello M, Schiano G, Guo Q, Mabillard H, Sayer JA, Olinger E, Terzi F, Devuyst O
Publication type: Article
Publication status: Published
Journal: Journal of the American Society of Nephrology
Year: 2026
Pages: epub ahead of print
Online publication date: 26/03/2026
Acceptance date: 02/04/2018
ISSN (print): 1046-6673
ISSN (electronic): 1533-3450
Publisher: Wolters Kluwer Health
URL: https://doi.org/10.1681/ASN.0000001077
DOI: 10.1681/ASN.0000001077
PubMed id: 41885939
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