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Advances in uromodulin biology and potential clinical applications

Nature Reviews Nephrology (2024)Cite this article

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Abstract

Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific glycoprotein secreted bidirectionally into urine and into the circulation, and it is the most abundant protein in normal urine. Although the discovery of uromodulin predates modern medicine, its significance in health and disease has been rather enigmatic. Research studies have gradually revealed that uromodulin exists in multiple forms and has important roles in urinary and systemic homeostasis. Most uromodulin in urine is polymerized into highly organized filaments, whereas non-polymeric uromodulin is detected both in urine and in the circulation, and can have distinct roles. The interactions of uromodulin with the immune system, which were initially reported to be a key role of this protein, are now better understood. Moreover, the discovery that uromodulin is associated with a spectrum of kidney diseases, including acute kidney injury, chronic kidney disease and autosomal-dominant tubulointerstitial kidney disease, has further accelerated investigations into the role of this protein. These discoveries have prompted new questions and ushered in a new era in uromodulin research. Here, we delineate the latest discoveries in uromodulin biology and its emerging roles in modulating kidney and systemic diseases, and consider future directions, including its potential clinical applications.

Key points

  • Most urinary uromodulin undergoes polymerization into filaments and has important roles in maintaining urinary homeostasis. This polymerization occurs on the apical membrane and is highly organized.

  • Non-polymeric uromodulin, an increasingly recognized form, has distinct kidney and systemic roles. Recognizing the specific form and site of action is crucial to understanding the function of uromodulin.

  • Acute kidney injury is characterized by uromodulin deficiency. Non-polymerizing uromodulin supplementation might improve the course of acute kidney injury and prevent the transition to chronic kidney disease.

  • Single-nucleotide polymorphisms in UMOD and PDILT are strongly linked to the risk and progression of chronic kidney disease. Whether this effect depends on expression of a specific form of uromodulin remains to be clarified.

  • Retention and aggregation of mutant uromodulin in the endoplasmic reticulum causes autosomal-dominant tubulointerstitial kidney disease. Clearance of mutant uromodulin might be a promising therapeutic approach.

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Fig. 1: Expression, function and structure of uromodulin.
Fig. 2: Distinct pathways of extracellular secretion of uromodulin.
Fig. 3: Interactions of uromodulin with immune cells.
Fig. 4: Contributions of uromodulin to kidney disease.
Fig. 5: Pathogenesis of autosomal-dominant tubulointerstitial kidney disease-UMOD.

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Acknowledgements

We thank all the members of the Ashkar laboratory, current and past collaborators, and other researchers in the related field. We disclose support for the research of this work from National Institute of Health, National Institute for Diabetes and Digestive and Kidney Diseases (R01DK111651 for TME and R00DK127216 for KAL), a VA Merit Award (5I01BX003935) for TME, and Takeda Science Foundation for AN.

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  1. Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA

    Azuma Nanamatsu, Larissa de Araújo, Kaice A. LaFavers & Tarek M. El-Achkar

  2. Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA

    Kaice A. LaFavers & Tarek M. El-Achkar

  3. Roudebush VA Medical Center, Indianapolis, IN, USA

    Tarek M. El-Achkar

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T.M.E. and A.N. researched data for the article. T.M.E., A.N. and K.A.L. made substantial contributions to discussions of the content. All authors wrote, reviewed or edited the manuscript before submission.

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Correspondence to Tarek M. El-Achkar.

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Competing interests

The authors have two patents related to uromodulin: Modified Tamm–Horsfall protein and related compositions and methods of use (US11053290B2 for T.M.E.) and Materials and methods for quantifying precursor Tamm–Horsfall protein (WO2022155432A1 for T.M.E. and K.A.L.). The other authors declare no competing interests.

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Nanamatsu, A., de Araújo, L., LaFavers, K.A. et al. Advances in uromodulin biology and potential clinical applications. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00881-7

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