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. 2021 Oct;35(10):e21874.
doi: 10.1096/fj.202100774R.

Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease

Annarita Di Mise  1 , Xiaofang Wang  2 , Hong Ye  2 , Lorenzo Pellegrini  3 , Vicente E Torres  2 , Giovanna Valenti  1
Affiliations

Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease

Annarita Di Mise et al. FASEB J. 2021 Oct.

Abstract

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.

Keywords: GPCRs; calcimimetics; calcium-sensing receptor; polycystic kidney disease; vaptans; vasopressin V2 receptor.

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Conflict of interest statement

LP is an employee and owns stock in Palladio Biosciences, Inc, the sponsor of lixivaptan. R568 was supplied by Amgen Inc.

Figures

FIGURE 1
FIGURE 1
Effect of lixivaptan and R568 treatment on renal cAMP levels or PKA activity. (A) Renal cAMP in PCK rats, expressed as pmol cAMP on mg of total proteins. (B) PKA activity in kidney homogenates in Pkd1 RC/RC mice, measured as units (U) on mg of total proteins. Data are expressed as means ± SEM, *p < .05 versus CTR
FIGURE 2
FIGURE 2
AMPK phosphorylation levels in PCK rats and Pkd1 RC/RC mice. (A–C) Representative blots for total AMPK or for pT172‐AMPK (pAMPK). (B) Densitometric analysis and statistical studies (means ± SEM) in PCK rats (n = 8, 4 animals per group and gender), **p < .01 versus CTR, $ p < .05 versus LXV. (D) Densitometric analysis and statistical studies (means ± SEM) in Pkd1 RC/RC mice (n = 8, 4 animals per group and gender), ****p < .0001 versus CTR, # p < .001 versus LXV, **p < .01 versus CTR, $ p < .05 versus LXV + R568
FIGURE 3
FIGURE 3
ERK phosphorylation levels in PCK rats and Pkd1 RC/RC mice. (A–C) Representative blots for total ERK1/2 or ERK1/2 phosphorylated at Thr185/Tyr187 (pERK 1/2). (B) Densitometric analysis and statistical studies (means ± SEM) in PCK rats (n = 10, 5 animals per group and gender), *p < .01 versus CTR. (D) Densitometric analysis and statistical studies (means ± SEM) in Pkd1 RC/RC mice (n = 10, 5 animals per group and gender), *p < .01 versus CTR and LXV, # p < .01 versus LXV
FIGURE 4
FIGURE 4
Effect of lixivaptan and R568 treatment on renal morphology in PCK rats. (A) Evaluation of the effect of the drugs on kidney weight expressed as percentage of body weight. Data are expressed as means ± SEM, ****p < .0001 versus CTR, *p < .05 versus CTR or LXV or LXV + R568. (B) Representative histological images of kidney cross‐sections (scale bars: 2 mm) stained with hematoxylin‐eosin for cyst volume analysis, showed in the histogram (C). Data are expressed as means ± SEM, *p < .05, ***p < .001 versus CTR, $$ p < .01 versus LXV + R568. (D) Representative histological images of transverse kidney sections (scale bars: 200 mm) stained with picrosirius red for fibrosis measurement, quantified in the histogram (E). Data are expressed as means ± SEM, ***p < .001, **p < .01, ****p < .0001 versus CTR
FIGURE 5
FIGURE 5
Lixivaptan and R568 treatment effect on renal morphology in Pkd1 RC/RC mice. (A) Evaluation of the effect of the drugs on kidney weight expressed as percentage of body weight. Data are expressed as means ± SEM, **p < .01, ****p < .0001 versus CTR, $ p < .05 versus LXV + R568. (B) Representative histological images of transverse kidney sections (scale bars: 1 mm) stained with hematoxylin‐eosin for cyst volume analysis, showed in the histogram (C). Data are expressed as means ± SEM, *p < .05, **p < .01, ***p < .001 versus CTR. (D) Representative histological images of kidney cross‐sections (scale bars: 100 mm) stained with picrosirius red for fibrosis measurement, quantified in the histogram (E). Data are expressed as means ± SEM, ***p < .001, ****p < .0001 versus CTR
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References

    1. Chebib FT, Torres VE. Autosomal dominant polycystic kidney disease: core curriculum 2016. Am J Kidney Dis. 2016;67(5):792‐810. doi: 10.1053/j.ajkd.2015.07.037 - DOI - PMC - PubMed
    1. Spithoven EM, Kramer A, Meijer E, et al. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival—an analysis of data from the ERA‐EDTA registry. Nephrol Dial Transplant. 2014;29(suppl 4):iv15‐iv25. doi: 10.1093/ndt/gfu017 - DOI - PMC - PubMed
    1. Sussman CR, Wang X, Chebib FT, Torres VE. Modulation of polycystic kidney disease by G‐protein coupled receptors and cyclic AMP signaling. Cell Signal. 2020;72:109649. doi: 10.1016/j.cellsig.2020.109649 - DOI - PMC - PubMed
    1. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407‐2418. doi: 10.1056/NEJMoa1205511 - DOI - PMC - PubMed
    1. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in later‐stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377(20):1930‐1942. doi: 10.1056/NEJMoa1710030 - DOI - PubMed

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