Kidney Week

Abstract: SA-PO0622

Lipocalin-2 Is Induced by Uromodulin Aggregates but Does Not Affect Kidney Disease Progression in UMOD-Related Autosomal Dominant Tubulointerstitial Kidney Disease

Session Information

• Monogenic Kidney Diseases: Tubular and Other
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Lake, Jennifer, Institut Necker Enfants Malades, Paris, Île-de-France, France

Jennifer Lake, PhD

• Mariniello, Marta, Universitat Zurich, Zürich, ZH, Switzerland

Marta Mariniello, PhD

• Terzi, Fabiola, Institut Necker Enfants Malades, Paris, Île-de-France, France

Fabiola Terzi, MD, PhD

• Devuyst, Olivier, Universitat Zurich, Zürich, ZH, Switzerland

Olivier Devuyst, MD, PhD

Background

The mechanisms driving progression of autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations (ADTKD-UMOD) remain poorly understood, limiting therapy development. Lipocalin-2 (LCN2) is an acute phase protein involved in innate immunity and in regulating intracellular iron homeostasis. As a marker of tubular stress, LCN2 has been implicated in kidney disease progression, but its role in ADTKD-UMOD is unknown.

Methods

We explored LCN2 expression and relevance in ADTKD-UMOD using humanized knock-in (KI) mouse models harboring UMOD mutations (Umod^C171Y, Umod^R186S, Umod^C125R) associated with variable disease progression. Urinary LCN2 levels were measured in ADTKD-UMOD patients. Kidney tubular (mIMCD3) cells stably expressing wild-type or mutant uromodulin (C170Y, R185S) were used to assess the impact of uromodulin aggregation on LCN2 induction. The potential role of LCN2 was tested by crossing Umod^R186S/+ mice with Lcn2^-/- mice and by analyzing markers of disease progression.

Results

LCN2 expression was markedly increased in kidneys and urine of Umod^R186S/+ and Umod^C125R/+ mice, and to a lesser extent in Umod^C171Y/+ mice, correlating with the amount of uromodulin aggregates in mutant kidneys. The strongest LCN2 increase was observed in the Umod^R186S/+ kidneys, located in the thick ascending limb (TAL) cells containing uromodulin toxic aggregates. Elevated LCN2 levels were also detected in the urine of patients harbouring UMOD mutations. LCN2 induction by specific mutant uromodulin aggregates was confirmed in the mIMCD3 cells, with a significant rescue observed when stimulating aggregate clearance with Torin-1. In Umod^R186SLcn2^-/- mice, deletion of LCN2 led to a significant decrease in iron deposits near TAL cells accumulating toxic uromodulin, but did not significantly alter uromodulin accumulation, interstitial inflammation or kidney fibrosis.

Conclusion

These findings identify LCN2 as a mutation-specific tubular stress marker in ADTKD-UMOD, strongly induced by intracellular accumulation of mutant uromodulin in TAL cells. While LCN2 contributes to iron handling, it does not drive fibrosis nor inflammation in the mutant kidneys, supporting its potential utility as a disease biomarker rather than a therapeutic target.

Funding

• Government Support – Non-U.S.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025v7rpsc3c