Kidney Week

Abstract: FR-PO723

Dual Targeting of the G Protein-Coupled Receptors CaSR and V2R for Treating Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

• Cystic Kidney Diseases: Clinical/Translational
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Di Mise, Annarita, University of Bari, Bari, Italy

Annarita Di Mise,

• Wang, Xiaofang, Mayo Clinic, Rochester, Minnesota, United States

Xiaofang Wang,

• Ye, Hong, Mayo Clinic, Rochester, Minnesota, United States

Hong Ye,

• Pellegrini, Lorenzo, Palladio Biosciences, Newtown, Pennsylvania, United States

Lorenzo Pellegrini,

• Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States

Vicente E. Torres,

• Valenti, Giovanna, University of Bari, Bari, Italy

Giovanna Valenti,

Background

ADPKD is the 4th leading cause of end stage renal disease in the US. It is caused by mutations in PKD1 or PKD2 genes, which lead to excessive cell proliferation and fluid secretion, and ultimately cyst formation and growth. Reduced resting cytosolic calcium (Ca²⁺) and increased cAMP levels, associated with the tonic action of vasopressin, are two central biochemical defects in ADPKD. Currently there is no cure for the disease. The vasopressin V2 receptor (V2R) antagonist tolvaptan is the only drug approved to delay the progression of ADPKD, however it causes serious idiosyncratic hepatocellular toxicity. Simulations on a multiscale computational model of drug-induced liver injury indicate that the novel V2R antagonist lixivaptan has a safer liver profile.
Here, we show that co-targeting two GPCRs, the Calcium Sensing Receptor (CaSR), which finely regulates Ca²⁺ homeostasis, and the V2R, using the calcimimetic R-568 in combination with lixivaptan, reduced cyst progression in two animal models of human PKD.

Methods

PCK rat and Pkd1^RC/RC mouse littermates were fed ground rodent chow without or with lixivaptan (0.5%) and R-568 (0.025% for rats and 0.04% for mice), alone or in combination, for 7 (rats) or 13 (mice) weeks.

Results

In PCK rats, lixivaptan induced a significant reduction in kidney weight, cyst and fibrosis volumes by 20%, 31% and 60%, respectively, compared to animals fed with standard diet. The combined treatment strongly decreased the same parameters by 24%, 46% and 73%, respectively. R-568 alone induced a significant reduction only in kidney weight by 9% and fibrosis volume by 52%. Similar results were obtained in Pkd1^RC/RC mice.

Conclusion

These data suggest an intriguing new application for two known drugs. The potential for synergy between these two compounds suggested in these animal studies warrants further investigation in clinical settings.

Funding

• Commercial Support –