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ResearchIn-Press PreviewCell biologyNephrology Open Access | 10.1172/JCI188792

Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates

Cary R. Boyd-Shiwarski,1 Rebecca T. Beacham,1 Jared A. Lashway,1 Katherine E. Querry,1 Shawn E. Griffiths,1 Daniel J. Shiwarski,2 Sophia A. Knoell,1 Nga H. Nguyen,1 Lubika J. Nkashama,1 Melissa N. Valladares,1 Anagha Bandaru,1 Allison L. Marciszyn,1 Jonathan Franks,3 Mara Sullivan,3 Simon C. Watkins,3 Aylin R. Rodan,4 Chou-Long Huang,5 Sean D. Stocker,6 Ossama B. Kashlan,1 and Arohan R. Subramanya7

1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, United States of America

2Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Utah, United States of America

5Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa, United States of America

6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

7Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

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Published June 10, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188792.
Copyright © 2025, Boyd-Shiwarski 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 June 10, 2025 - Version history
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Abstract

To maintain potassium homeostasis, the kidney’s distal convoluted tubule (DCT) evolved to convert small changes in blood [K+] into robust effects on salt reabsorption. This process requires NaCl cotransporter (NCC) activation by the With-No-Lysine (WNK) kinases. During hypokalemia, the Kidney-Specific WNK1 isoform (KS-WNK1) scaffolds the DCT-expressed WNK signaling pathway within biomolecular condensates of unknown function termed WNK bodies. Here, we show that KS-WNK1 amplifies kidney tubule reactivity to blood [K+], in part via WNK bodies. Genetically modified mice with targeted condensate disruption trap the WNK pathway, causing renal salt wasting that is more pronounced in females. In humans, WNK bodies accumulate as plasma potassium falls below 4.0 mmol/L, suggesting that the human DCT experiences the stress of potassium deficiency even when [K+] is in the low-normal range. These data identify WNK bodies as kinase signal amplifiers that mediate tubular [K+] responsiveness, nephron sexual dimorphism, and blood pressure salt-sensitivity. Our results illustrate how biomolecular condensate specialization can optimize a mammalian physiologic stress response that impacts human health.

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