Kidney Week

Abstract: FR-PO0085

Development of Novel Animal Models to Study Vasopressin-Independent Pathways in ADPKD

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

• Zuchowski, Yvonne, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yvonne Zuchowski

• Arroyo Ornelas, Juan Pablo, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Juan Pablo Arroyo Ornelas, MD, PhD

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited cause of end-stage-kidney-disease in the world. Currently, the only FDA approved medication to treat ADPKD is the type-2 vasopressin receptor antagonist, tolvaptan. V2R antagonism has some moderate beneficial effects in a certain subset of patients, but the high costs and extensive side-effect profile limits its wide spread use. Therefore, to identify novel vasopressin-independent signaling pathways that are relevant for cyst growth in vivo, we set out to develop novel, kidney-specific, mouse models of ADPKD.

Methods

We crossed the doxycycline inducible Pkd1^fl/fl;Pax8-rtTA;Tet-o-Cre with the Avpr2^fl/fl mouse to generate the Pkd1^fl/fl;Avpr2^fl/flPax8-rtTA;Tet-o-Cre (PKD1-V2R KO) mouse which lacks expression of Pkd1 and Avpr2 (the gene that codes for V2R). Our group previously showed that vasopressin is made in the kidney, therefore we crossed the Avp^fl/fl mouse with the Pkd1^fl/fl;Pax8-rtTA;Tet-o-Cre to generate the Pkd1^fl/fl;Avp^fl/flPax8-rtTA;Tet-o-Cre (PKD1-AVP KO).

Results

We induced recombination with two different strategies: 1) Early – 2% doxycycline pellet diet at P0 and 2) Late – 0.625% doxycycline pellet diet at weaning (P21) for 3 weeks each. Mice were then euthanized and kidneys collected. We found that relative to PKD1 single KO mice, PKD1-V2R KO had smaller KW/BW ratio in the early (0.1238 +/- 0.22 vs 0.0095 +/- 0.038) but not the late induction group (0.01476 +/- 0.0033 vs 0.01457 +/- 0.0016). While the PKD1-AVP KO had larger KW/BW ratio in both the early and late induction groups (0.1238 +/- 0.22 vs 0.1511 +/- 0.050) and (0.01476 +/- 0.0033 vs 0.01820 +/- 0.0053).

Conclusion

These results show that we have generated two new mouse models that recapitulate the ADPKD phenotype in the absence of V2R signaling or kidney-tubule-derived vasopressin. We confirmed prior observations that suggest early antagonism of V2R can modify cyst growth. We also show that the absence of kidney-tubule-derived vasopressin worsens the cystic phenotype. These new models and observations will allow to study vasopressin independent pathways that modify cyst growth, which will open the door to the development of novel therapeutic approaches for ADPKD.

Funding

• NIDDK Support