Kidney Week

Abstract: SA-PO0095

A Urate-Driven PDE4-AMPK Axis Regulates AQP2 Trafficking and Mitigates Tolvaptan-Induced Aquaresis in ADPKD

Session Information

• ADPKD and Cystic Kidney Disease - 3
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Hadla, Mohamad, Mayo Clinic in Florida, Jacksonville, Florida, United States

Mohamad Hadla, PhD

• Mardirossian, Jean Marc Garbis, Mayo Clinic in Florida, Jacksonville, Florida, United States

Jean Marc Garbis Mardirossian, MS

• Bichet, Daniel G., Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada

Daniel G. Bichet, MD, DrMed

• Borghol, Abdul Hamid, Mayo Clinic in Florida, Jacksonville, Florida, United States

Abdul Hamid Borghol, MD

• Abboud, Georges, Mayo Clinic in Florida, Jacksonville, Florida, United States

Georges Abboud, PhD

• Ghanem, Ahmad, Mayo Clinic in Florida, Jacksonville, Florida, United States

Ahmad Ghanem, MD

• Chini, Eduardo N., Mayo Clinic in Florida, Jacksonville, Florida, United States

Eduardo N. Chini, MD, PhD

• Harris, Peter C., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Torres, Vicente E., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States

Vicente E. Torres, MD, PhD

• Alper, Seth L., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Seth L. Alper, MD, PhD, FASN

• Vallon, Volker, University of California San Diego Department of Medicine, La Jolla, California, United States

Volker Vallon, MD, FASN

• Chebib, Fouad T., Mayo Clinic in Florida, Jacksonville, Florida, United States

Fouad T. Chebib, MD, FASN

Background

Aquaporin 2 (AQP2) trafficking is canonically regulated by AVP–V2R signaling, but aquaretic effects limit vaptan tolerability in ADPKD. Noncanonical mechanisms may offer complementary strategies to reduce aquaretic burden. We examined intracellular urate as a regulator of AQP2 trafficking.

Methods

AQP2 trafficking was quantified in polarized mIMCD3 AQP2-GFP cells by confocal microscopy. Intracellular urate levels and cAMP-PKA-AMP-AMPK signaling were measured. GLUT9b/ABCG2 transport and PDE signaling were interrogated using siRNA and pharmacologic perturbations. In vivo effects were evaluated in Pkd1^RC/RC mice treated with tolvaptan ± probenecid. Probenecid was also evaluated in a phase 2 trial in tolvaptan-treated individuals.

Results

Apical urate (50-500 µM) induced concentration-dependent apical membrane accumulation of AQP2, independent of V2R signaling. Intracellular urate set by opposing GLUT9b influx and ABCG2 efflux; ABCG2 inhibition by probenecid increased intracellular urate and promoted apical AQP2 accumulation. Urate suppressed cAMP-PKA signaling (~30% reduction), increased AMP (~40%), and doubled AMPK phosphorylation within 1 h. Urate-stimulated apical AQP2 accumulation required endocytosis and was associated with post-endocytic apical trafficking.
In Pkd1^RC/RC mice, probenecid reduced tolvaptan-induced urine output (5.1 ± 1.0 to 2.6 ± 0.4 mL/day, p<0.01) and water intake (10.1 ± 1.1 to 5.4 ± 0.6 mL/day, p<0.01), while preserving improved cyst outcomes.
In individuals with ADPKD on tolvaptan, probenecid reduced 24-h urine volume by 30.2 ± 11.1% (p<0.0001) and decreased nocturia.

Conclusion

Intracellular urate mediates a vasopressin-independent signaling axis linking GLUT9b/ ABCG2 urate transport to PDE4–AMPK activation and AQP2 trafficking (Figure). Targeting this pathway improves vaptan tolerability in ADPKD by reducing aquaresis while preserving cyst growth inhibition.

Urate activates a PDE4–AMPK axis to drive AQP2 trafficking, enhancing water reabsorption and reducing aquaresis.

Funding

• NIDDK Support