Repurposing calcium-sensing receptor activator drug cinacalcet for ADPKD treatment

Transl Res. 2023 Oct 30:S1931-5244(23)00177-9. doi: 10.1016/j.trsl.2023.10.005. Online ahead of print.ABSTRACTADPKD is characterized by progressive cyst formation and enlargement leading to kidney failure. 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 regulator of epithelial ion transport. FDA-approved CaSR activator cinacalcet can reduce cAMP-induced Cl- and fluid secretion in various epithelial cells by activating phosphodiesterases (PDE) that hydrolyze cAMP. Since elevated cAMP is a key mechanism of ADPKD progression by promoting cell proliferation, cyst formation and enlargement (via Cl- and fluid secretion), here we tested efficacy of cinacalcet in cell and animal models of ADPKD. Cinacalcet treatment reduced cAMP-induced Cl- secretion and CFTR activity in MDCK cells as suggested by ∼70 % lower short-circuit current (Isc) changes in response to forskolin and CFTRinh-172, respectively. Cinacalcet treatment inhibited forskolin-induced cAMP elevation by 60 % in MDCK cells, and its effect was completely reversed by IBMX (PDE inhibitor). In MDCK cells treated with forskolin, cinacalcet treatment concentration-dependently reduced cell proliferation, cyst formation and cyst enlargement by up to 50 % without affecting cell viability. Cinacalcet treatment ...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Source Type: research