Abstract: FR-PO0679
Thyroxine as a Pleiotropic Modulator in ADPKD: Insights from Engineered Tubules, In Vivo Models, and Patients
Session Information
- Cystic Kidney Diseases: Basic and Translational Research
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Lavecchia, Angelo Michele, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Trillini, Matias, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Locatelli, Laura, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Del Vecchio, Alice, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Cerullo, Domenico, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Villa, Alessandro, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Peracchi, Tobia, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Brizi, Valerio, IRCCS Istituto di Ricerche Farmacologiche Mario Negri Centro Anna Maria Astori, Bergamo, Lombardy, Italy
- Buttó, Sara, IRCCS Istituto di Ricerche Farmacologiche Mario Negri Centro Anna Maria Astori, Bergamo, Lombardy, Italy
- Corna, Daniela, IRCCS Istituto di Ricerche Farmacologiche Mario Negri Centro Anna Maria Astori, Bergamo, Lombardy, Italy
- Rubis, Nadia, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Guarinoni, Chiara, Istituto di Ricerche Farmacologiche Mario Negri Centro Aldo e Cele Dacco, Ranica, Lombardy, Italy
- Remuzzi, Giuseppe, IRCCS Istituto di Ricerche Farmacologiche Mario Negri Centro Anna Maria Astori, Bergamo, Lombardy, Italy
- Xinaris, Christodoulos, IRCCS Istituto di Ricerche Farmacologiche Mario Negri Centro Anna Maria Astori, Bergamo, Lombardy, Italy
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a rare monogenic disease, characterized by the formation of multiple cysts that cause gradual loss of renal function. To date there is no effective cure for this disease. The involvement of multiple dysregulated cellular pathways in cyst formation suggests that a pleiotropic modulator may offer therapeutic benefit. Thyroid hormone (TH) could be such modulator, known to influence cell growth, proliferation, metabolism, differentiation, and apoptosis.
Methods
To assess the therapeutic potential of thyroid hormones (THs) and their analogues, we engineered 3D polycystic tubules from ADPKD patient cells and treated them accordingly. Cyst number and size were quantified pre- and post- treatment. To validate the efficacy of the treatment in vivo, we administered thyroxine (T4) to PCK rats, a model of polycystic kidney disease. In parallel, we conducted an exploratory clinical study to evaluate TH imbalances and their association with disease progression in ADPKD patients.
Results
THs—and particularly T4—significantly reduced both cyst formation and growth in the engineered tubules. Mechanistic studies revealed that T4 exerts its effects by binding to the αvβ3 integrin, leading to activation of antioxidant pathways and inhibition of proliferative ones. In vivo, PCK rats exhibited lower serum TH levels compared to healthy controls. T4 treatment resulted in a significant reduction in renal macrocystic area compared to vehicle-treated animals, confirming its anti-cystogenic effect in vivo. To further investigate the role of THs in ADPKD, we conducted an exploratory clinical study. The data revealed that the declining in renal function correlates with reduced levels of free T3—the active form of TH—and elevated levels of reverse T3, an inactive TH metabolite. These findings suggest that TH imbalance may be a contributing factor in the progression of ADPKD.
Conclusion
Collectively, our results provide compelling evidence that T4 contributes to ADPKD pathogenesis and represents a promising therapeutic candidate to reduce cystogenesis and preserve renal function.