Uromodulin modulates mitochondria and kidney tubule resilience
Ronak Lakhia, … , Chunzi Song, Vishal Patel
Ronak Lakhia, … , Chunzi Song, Vishal Patel
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e193829. https://doi.org/10.1172/JCI193829.
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Commentary

Uromodulin modulates mitochondria and kidney tubule resilience

Abstract

Uromodulin is the most abundant protein in human urine, playing diverse roles, from providing frontline defense against uropathogens to regulating electrolyte balance via modulation of ion channels and cotransporters. In this issue of the JCI, Nanamatsu et al. unveil an alternatively spliced isoform of uromodulin that was dynamically induced in response to oxidative stress and tubular injury. Unlike the canonical secreted form, this isoform was retained in the cell, where it interacted with solute carrier proteins primarily localized to the mitochondrial membrane. Through these interactions, it modulated mitochondrial energetics and enhanced tubular cell resilience to injury. These findings broaden our understanding of uromodulin’s multifaceted functions, uncover an adaptive mechanism by which the kidney responds to cellular stress, and open avenues for therapeutic strategies targeting kidney injury and repair.

Authors

Ronak Lakhia, Chunzi Song, Vishal Patel

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Figure 1

An AS-UMOD isoform of uromodulin promotes tubular recovery following injury.

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An AS-UMOD isoform of uromodulin promotes tubular recovery following inj...
Under homeostatic conditions, cells in the thick ascending limb produce full-length uromodulin, which is trafficked to the apical surface or secreted into the urinary space. In response to tubular stress, such as mild AKI, TAL cells also produce AS-UMOD. This isoform is retained in the cell, where it interacts with mitochondrial transporters to enhance cellular energetics, including ATP production, and confers resilience to injury. This adaptive mechanism is lost during severe AKI. However, therapeutic administration of splice-switching antisense oligonucleotides (SSOs) can pharmacologically elevate AS-UMOD levels even in severe AKI, resulting in reduced kidney damage.