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 Pkd1^RC/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 Pkd1^RC/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.

中文翻译：

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GPCRs CaSR 和 V2R 双重靶向作为常染色体显性多囊肾病治疗策略的临床前评价

由PKD1或PKD2突变引起的常染色体显性多囊肾病 (ADPKD)基因，其特征是囊肿的发育和生长导致进行性肾脏增大。与加压素的强直作用相关的静息细胞溶质钙减少和 cAMP 水平升高是 ADPKD 的两个主要生化缺陷。在这里，我们展示了共同靶向两种 GPCR，即加压素 V2 受体 (V2R) 和钙传感受体，使用新型 V2R 拮抗剂 lixivaptan 与拟钙剂 R-568 联合使用，可减少人类 PKD 的两种动物模型中的囊肿进展。根据计算模型结果和初步临床证据，与托伐普坦相比，利西伐坦有望具有更安全的肝脏特征，托伐普坦是唯一一种获准延缓 PKD 进展的药物。PCK 大鼠和Pkd1 ^RC/RC单独或联合使用利西伐普坦 (0.5%) 和 R-568 (大鼠为 0.025%，小鼠为 0.04%) 喂养同窝小鼠 7 周（大鼠）或 13 周（小鼠）。在 PCK 大鼠中，与未治疗的动物相比，联合治疗使肾脏重量、囊肿和纤维化体积分别显着降低了 20%、49% 和 73%。在Pkd1 ^RC/RC小鼠，相同的参数分别降低了 20%、56% 和 69%。在这两种情况下，联合治疗在名义上似乎比单独使用的单个药物更有效。这些数据表明两种现有药物在 PKD 治疗中的一个有趣的新应用。如果在适当的临床研究中得到证实，这些动物研究中建议的这两种化合物之间的协同作用的潜力将代表 ADPKD 治疗的可喜进步。