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ResearchIn-Press PreviewCell biologyNephrology Open Access | 10.1172/JCI183343

Alternative splicing of uromodulin enhances mitochondrial metabolism for adaptation to stress in kidney epithelial cells

Azuma Nanamatsu,1 George J. Rhodes,1 Kaice A. LaFavers,2 Radmila Micanovic,1 Virginie Lazar,1 Shehnaz Khan,1 Daria Barwinska,1 Shinichi Makino,1 Amy Zollman,1 Ying-Hua Cheng,1 Emma H. Doud,3 Amber L. Mosley,3 Matthew J. Repass,4 Malgorzata M. Kamocka,1 Aravind Baride,5 Carrie L. Phillips,5 Katherine J. Kelly,1 Michael T. Eadon,1 Jonathan Himmelfarb,6 Matthias Kretzler,7 Robert L. Bacallao,1 Pierre C. Dagher,1 Takashi Hato,1 and Tarek M. El-Achkar1

1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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1Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, United States of America

2Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, United States of America

3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America

4Cellular Response Technologies Core, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Medicine, University of Michigan, Ann Arbor, United States of America

8Department of Medicine, Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianpolis, United States of America

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Published April 8, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI183343.
Copyright © 2025, Nanamatsu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 8, 2025 - Version history
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Abstract

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 up-regulated 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 novel therapeutic intervention for AKI.

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