Alternative splicing of uromodulin enhances mitochondrial metabolism for adaptation to stress in kidney epithelial cells
In the kidney, cells of thick ascending limb of the loop of Henle (TAL) are resistant to ischemic injury, despite high energy demands. This adaptive metabolic response is not fully understood even though the integrity of TAL cells is essential for recovery from acute kidney injury (AKI). TAL cells uniquely express uromodulin, the most abundant protein secreted in healthy urine. Here, we demonstrate that alternative splicing generates a conserved intracellular isoform of uromodulin, which contributes to metabolic adaptation of TAL cells. This splice variant was induced by oxidative stress and was upregulated by AKI that is associated with recovery, but not by severe AKI and chronic kidney disease (CKD). This intracellular variant was targeted to the mitochondria, increased NAD+ and ATP levels, and protected TAL cells from hypoxic injury. Augmentation of this variant using antisense oligonucleotides after severe AKI improved the course of injury. These findings underscore an important role of condition-specific alternative splicing in adaptive energy metabolism to hypoxic stress. Enhancing this protective splice variant in TAL cells could become a therapeutic intervention for AKI.
Authors
- Shehnaz Khan
- Carrie L. Phillips (ORCID: https://orcid.org/0000-0002-0256-0736)
- Shin‐ichi Makino (ORCID: https://orcid.org/0000-0003-0135-0435)
- Emma H. Doud (ORCID: https://orcid.org/0000-0003-0049-0073)
- Azuma Nanamatsu (ORCID: https://orcid.org/0000-0002-8512-0161)
- Robert L. Bacallao (ORCID: https://orcid.org/0000-0002-5703-5701)
- Radmila Micanovic (ORCID: https://orcid.org/0000-0002-8151-0234)
- Takashi Hato (ORCID: https://orcid.org/0000-0002-0446-6575)
- Katherine J. Kelly (ORCID: https://orcid.org/0000-0001-7244-9657)
- Matthew J. Repass
- Aravind Baride (ORCID: https://orcid.org/0000-0001-7582-1522)
- Amber L. Mosley (ORCID: https://orcid.org/0000-0001-5822-2894)
- Ying‐Hua Cheng (ORCID: https://orcid.org/0000-0001-7871-8141)
- Michael T. Eadon (ORCID: https://orcid.org/0000-0003-3066-2876)
- Jonathan Himmelfarb (ORCID: https://orcid.org/0000-0002-3319-1224)
- Malgorzata M. Kamocka (ORCID: https://orcid.org/0009-0003-2944-4094)
- Matthias Kretzler (ORCID: https://orcid.org/0000-0003-4064-0582)
- Virginie Lazar
- Pierre C. Dagher (ORCID: https://orcid.org/0000-0003-3321-5561)
- Daria Barwinska (ORCID: https://orcid.org/0000-0002-0776-3030)
- Kaice A. LaFavers (ORCID: https://orcid.org/0000-0003-2052-6248)
- Tarek M. El‐Achkar (ORCID: https://orcid.org/0000-0003-4645-3614)
- Amy Zollman
- George Rhodes
Institutions
- University of Michigan (US)
- Richard L. Roudebush VA Medical Center (US)
- Hypertension Institute (US)
- Response Technologies (United States) (US)
- Institute of Bioinformatics (IN)
- Czech Academy of Sciences, Institute of Physiology (CZ)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1172/jci183343
- Citations
- 11
- Primary Topic
- Birth, Development, and Health
- Type
- article
- Field-Weighted Citation Impact
- 38.44
Funders
- Takeda Science Foundation
- National Institutes of Health
- School of Medicine, Indiana University
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences