Journal of the American Society of Nephrology : JASN · 2026
Lipocalin-2 Is Induced by Uromodulin Aggregates without Affecting Kidney Disease Progression in Autosomal Dominant Tubulointerstitial Kidney Disease- UMOD.
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Lake Jennifer, Mariniello Marta, Schiano Guglielmo, Guo Qin, Mabillard Holly, Sayer John A, Olinger Eric, Terzi Fabiola, Devuyst Olivier
Аннотация
KEY POINTS: Lipocalin-2 upregulation paralleled intracellular uromodulin aggregates in mouse and cellular models of autosomal dominant tubulointerstitial kidney disease because of pathogenic uromodulin. The induction of lipocalin-2 was triggered by mutant uromodulin accumulation and endoplasmic reticulum stress in tubular cells. 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.
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease due to pathogenic UMOD variants (ADTKD- UMOD ) 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.
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 UMOD. 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 UMOD 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 UMOD (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 UMOD accumulation, interstitial inflammation, or fibrosis.
CONCLUSIONS: LCN2 was induced by intracellular UMOD 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.
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease due to pathogenic UMOD variants (ADTKD- UMOD ) 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.
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 UMOD. 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 UMOD 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 UMOD (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 UMOD accumulation, interstitial inflammation, or fibrosis.
CONCLUSIONS: LCN2 was induced by intracellular UMOD 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.