TY - JOUR
T1 - Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease
AU - Di Mise, Annarita
AU - Wang, Xiaofang
AU - Ye, Hong
AU - Pellegrini, Lorenzo
AU - Torres, Vicente E.
AU - Valenti, Giovanna
N1 - Funding Information:
We thank Amgen, Inc for providing the calcimimetic R‐568. This research was funded by Regional project POR Puglia Innonetwork (grant number H6GG787 to GV), by the National Institute of Diabetes and Digestive and Kidney Diseases (grant numbers DK‐44863 and DK‐90728 to VET) and by the Mayo Clinic Robert M. and Billie Kelley Pirnie Translational PKD Research Center. Annarita Di Mise is supported by “Attrazione e Mobilità dei Ricercatori, PON “R&I” 2014–2020, Azione I.2” (code AIM1893457‐3, linea 1).
Publisher Copyright:
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2021/10
Y1 - 2021/10
N2 - Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations of PKD1 or PKD2 genes, is characterized by development and growth of cysts causing progressive kidney enlargement. Reduced resting cytosolic calcium and increased cAMP levels associated with the tonic action of vasopressin are two central biochemical defects in ADPKD. Here we show that co-targeting two GPCRs, the vasopressin V2 receptor (V2R) and the calcium sensing receptor, using the novel V2R antagonist lixivaptan in combination with the calcimimetic R-568, reduced cyst progression in two animal models of human PKD. Lixivaptan is expected to have a safer liver profile compared to tolvaptan, the only drug approved to delay PKD progression, based on computational model results and initial clinical evidence. PCK rat and Pkd1RC/RC mouse littermates were fed 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. In PCK rats, the combined treatment strongly decreased kidney weight, cyst and fibrosis volumes by 20%, 49%, and 73%, respectively, compared to untreated animals. In Pkd1RC/RC mice, the same parameters were reduced by 20%, 56%, and 69%, respectively. In both cases the combined treatment appeared nominally more effective than the individual drugs used alone. These data point to an intriguing new application for two existing drugs in PKD treatment. The potential for synergy between these two compounds suggested in these animal studies, if confirmed in appropriate clinical investigations, would represent a welcome advancement in the treatment of ADPKD.
AB - Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations of PKD1 or PKD2 genes, is characterized by development and growth of cysts causing progressive kidney enlargement. Reduced resting cytosolic calcium and increased cAMP levels associated with the tonic action of vasopressin are two central biochemical defects in ADPKD. Here we show that co-targeting two GPCRs, the vasopressin V2 receptor (V2R) and the calcium sensing receptor, using the novel V2R antagonist lixivaptan in combination with the calcimimetic R-568, reduced cyst progression in two animal models of human PKD. Lixivaptan is expected to have a safer liver profile compared to tolvaptan, the only drug approved to delay PKD progression, based on computational model results and initial clinical evidence. PCK rat and Pkd1RC/RC mouse littermates were fed 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. In PCK rats, the combined treatment strongly decreased kidney weight, cyst and fibrosis volumes by 20%, 49%, and 73%, respectively, compared to untreated animals. In Pkd1RC/RC mice, the same parameters were reduced by 20%, 56%, and 69%, respectively. In both cases the combined treatment appeared nominally more effective than the individual drugs used alone. These data point to an intriguing new application for two existing drugs in PKD treatment. The potential for synergy between these two compounds suggested in these animal studies, if confirmed in appropriate clinical investigations, would represent a welcome advancement in the treatment of ADPKD.
KW - GPCRs
KW - calcimimetics
KW - calcium-sensing receptor
KW - polycystic kidney disease
KW - vaptans
KW - vasopressin V2 receptor
UR - http://www.scopus.com/inward/record.url?scp=85115820073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85115820073&partnerID=8YFLogxK
U2 - 10.1096/fj.202100774R
DO - 10.1096/fj.202100774R
M3 - Article
C2 - 34486176
AN - SCOPUS:85115820073
VL - 35
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 10
M1 - e21874
ER -