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ResearchIn-Press PreviewCell biologyNephrology Open Access | 10.1172/JCI197021

GLUT9b- and ABCG2-mediated collecting duct urate transport uncover a vasopressin-independent mechanism of renal water reabsorption

Mohamad Hadla,1 Jean Marc Mardirossian,1 Daniel G. Bichet,2 Abdul Hamid Borghol,1 Georges Abboud,1 Ahmad Ghanem,1 Eduardo N. Chini,3 Peter C. Harris,1 Vicente E. Torres,1 Seth L. Alper,5 Volker Vallon,6 and Fouad T. Chebib7

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Hadla, M. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Mardirossian, J. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

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1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

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1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Abboud, G. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

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1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Chini, E. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Harris, P. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Torres, V. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Alper, S. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Vallon, V. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, United States of America

2Departments of Medicine and of Pharmacology and Physiology, University of Montreal, Montreal, Canada

3Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Depar, Mayo Clinic, Jacksonville, United States of America

4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States of America

5Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, United States of America

6Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

7Division of Nephrology and Hypertension, Mayo Cinic, Jakconville, United States of America

Find articles by Chebib, F. in: PubMed | Google Scholar |

Published June 16, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI197021.
Copyright © 2026, Hadla 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 16, 2026 - Version history
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Abstract

Renal water reabsorption is classically regulated by vasopressin V2 receptor (V2R) signaling through cyclic AMP and protein kinase A, driving apical accumulation of aquaporin-2 (AQP2). However, collecting duct water handling is also modulated by vasopressin-independent mechanisms. Here, we examined intracellular soluble urate as a vasopressin-independent regulator of AQP2 trafficking. Intracellular urate accumulation in collecting duct cells was mediated by enhanced apical urate uptake via GLUT9b and reduced apical urate efflux through ABCG2, triggering phosphodiesterase-4 activation, reduced cAMP, and downstream AMP-activated protein kinase (AMPK) activation. The resulting AQP2 accumulation at the apical membrane was independent of V2R signaling, required ongoing endocytosis and was associated with features of post-endocytic apical trafficking of internalized AQP2. In vivo ABCG2 inhibition with probenecid increased apical AQP2 abundance and markedly attenuated tolvaptan-induced polyuria in both wild-type and Pkd1RC/RC autosomal dominant polycystic kidney disease (ADPKD) mice in a uricase-independent manner, while preserving tolvaptan’s ADPKD-modifying efficacy. In a Phase 2 trial with tolvaptan-treated ADPKD patients, probenecid reduced urine volume and nocturia frequency. Together, these findings support a vasopressin-independent urate–AMPK–AQP2 pathway that regulates renal water handling and, in a preclinical ADPKD model, can uncouple cyst growth attenuation from the dose-limiting aquaretic effects of V2R antagonism.

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