Kidney Week

Abstract: FR-PO348

Repurposing Calcium-Sensing Receptor Activator Cinacalcet for Autosomal Dominant Polycystic Kidney Disease Treatment

Session Information

• Genetic Diseases: Models, Mechanisms, Treatments
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Yottasan, Pattareeya, University of California San Francisco, San Francisco, California, United States

Pattareeya Yottasan,

• Chu, Qi Tifany, University of California San Francisco, San Francisco, California, United States

Qi Tifany Chu,

• Cil, Onur, University of California San Francisco, San Francisco, California, United States

Onur Cil,

Background

ADPKD is characterized by progressive cyst formation and enlargement leading to renal failure. Elevated cAMP is a key mechanism of ADPKD progression by promoting cell proliferation, cystogenesis, and cyst enlargement (via Cl^- and fluid secretion). V2 receptor antagonist tolvaptan is currently the only FDA-approved treatment for ADPKD; however, it can cause serious adverse effects including hepatotoxicity. There remains an unmet clinical need for effective and safe treatments for ADPKD. The extracellular Ca²⁺-sensing receptor (CaSR) is a major regulator of ion transport in kidney tubules and ADPKD cyst epithelia. Cinacalcet is an FDA-approved CaSR activator used for treatment of hyperparathyroidism associated with CKD and renal failure. We recently showed that cinacalcet has marked antisecretory effects in human intestinal cell and mouse models of cholera by activating phosphodiesterases (PDE) that hydrolyze cAMP (JCI Insight 2021, 6:e146823). Since elevated cAMP is the key shared pathophysiological mechanism for Cl^- and fluid secretion in cholera and ADPKD, we hypothesize that cinacalcet can reduce cyst enlargement in ADPKD.

Methods

We studied the effects of cinacalcet on Cl^- secretion, investigated its mechanisms of action; and tested its efficacy on cyst enlargement in MDCK cells and a mouse model of ADPKD.

Results

Cinacalcet (30 μM) pretreatment inhibited cAMP-induced Cl^- secretion and CFTR activity in MDCK cells as suggested by ~70% lower short-circuit current (I_sc) changes in response to forskolin and CFTR_inh-172, respectively. Cinacalcet pretreatment inhibited forskolin-induced cAMP elevation by 60% in MDCK cells, and its effect was completely reversed by PDE inhibitor IBMX. In MDCK cells grown in collagen matrix and treated with forskolin, cinacalcet treatment (1-10 μM, Day 6 onward) concentration-dependently reduced cyst enlargement by up to 50% at Day 12 without affecting cell viability (assayed by Alamar blue). In preliminary studies, cinacalcet treatment (30 mg/kg/day for 7 days) reduced renal cyst enlargement in Pkd1flox;KspCre mice.

Conclusion

Cinacalcet reduces cyst enlargement in cell and mouse models of ADPKD by reducing cAMP via PDE activation. Considering its efficacy shown here, and favorable safety profile including extensive post-approval data, cinacalcet can be repurposed as a novel ADPKD treatment.

Funding

• NIDDK Support