Kidney Week

Abstract: FR-PO0081

Expression of the Polycystin-1 C-Terminal Fragment Suppresses Cystic Phenotype in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 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

• Zielinski, Karina, Yale School of Medicine Department of Cellular & Molecular Physiology, New Haven, Connecticut, United States

Karina Zielinski

• Rai, Victoria, Yale School of Medicine Department of Cellular & Molecular Physiology, New Haven, Connecticut, United States

Victoria Rai

• Gresko, Nikolay P., Yale School of Medicine Department of Cellular & Molecular Physiology, New Haven, Connecticut, United States

Nikolay P. Gresko

• Rajendran, Vanathy, Yale School of Medicine Department of Cellular & Molecular Physiology, New Haven, Connecticut, United States

Vanathy Rajendran

• Dong, Ke, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Ke Dong, MD

• Somlo, Stefan, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Stefan Somlo, MD

• Caplan, Michael J., Yale School of Medicine Department of Cellular & Molecular Physiology, New Haven, Connecticut, United States

Michael J. Caplan, MD, PhD

Background

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation and expansion of fluid-filled renal cysts. Mutations in PKD1, which encodes polycystin-1 (PC1), account for ~85% of ADPKD cases. PC1 possesses domains conserved among adhesion GPCRs (aGPCRs), suggesting that it may exhibit receptor properties mimicking those of canonical aGPCRs. By interrogating the aGPCR-like properties of PC1, we have previously generated a version of PC1 that lacks the N-terminal fragment (PC1ΔNTF) and behaves like a constitutively active aGPCR. Here, we investigate whether expression of PC1ΔNTF is sufficient to suppress cystic disease in an orthologous murine conditional Pkd1-KO model.

Methods

We generated a novel murine model in which Pkd1 inactivation is doxycycline-inducible and expression of PC1ΔNTF is tamoxifen-inducible (Pkd1fl/fl; Pax8 rtTa; TetO-Cre; Rosa26 FlpoER/FSF-PC1ΔNTF). Mice were induced with doxycycline between 4-6 weeks, administered tamoxifen between 9-10 weeks, and sacrificed at 16 weeks. We assessed kidney weight/body weight ratio (2KW/BW), cystic index, and expression levels of gene transcripts previously demonstrated to influence the cilia-dependent cyst activation (CDCA) pathway.

Results

Expression of PC1ΔNTF at early-stage disease (10 weeks) results in significantly reduced 2KW/BW at late-stage disease (16 weeks) compared to Pkd1-KO mice that do not express PC1ΔNTF. Cystic index is also comparably reduced in Pkd1-KO mice expressing PC1ΔNTF at 16 weeks. This indicates that expression of PC1ΔNTF is sufficient to suppress cystic disease. We observed a trending reduction in the expression levels of CDCA-related Glis2 and Anks3 transcripts in Pkd1-KO mice expressing PC1ΔNTF compared to Pkd1-KO mice that do not express PC1ΔNTF, suggesting that expression of constitutively active PC1 inhibits the CDCA pathway. Assessment of additional molecular changes altered by expression of PC1ΔNTF is currently ongoing.

Conclusion

Expression of the PC1 C-terminal fragment is sufficient to suppress cystic disease in a mouse model of ADPKD. These results suggest that constitutive activation of PC1's putative receptor function could constitute a therapeutic option for intervention in ADPKD.

Funding

• NIDDK Support – Estuary Biotherapeutics