title: Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of ESRD. A central defect associated with ADPKD pathology is elevated levels of 3', 5'-cyclic AMP (cAMP). Compounds such as tolvaptan and pasireotide, which indirectly reduce adenylyl cyclase 6 (AC6) activity, have hence proven effective in slowing cyst progression. Here, we tested the efficacy of these compounds individually and in combination in a hypomorphic PKD1 model, Pkd1(R3277C/R3277C) (Pkd1(RC/RC)), in a 5-month preclinical trial. Initially, the Pkd1(RC/RC) model was inbred into the C57BL/6 background, minimizing disease variability, and the pathogenic effect of elevating cAMP was confirmed by treatment with the AC6 stimulant desmopressin. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression and in combination showed a clear additive effect. Furthermore, combination treatment significantly reduced cystic and fibrotic volume and decreased cAMP to wild-type levels. We also showed that Pkd1(RC/RC) mice experience hepatic hypertrophy that can be corrected by pasireotide. The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD.
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hopp
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Hommerding
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.affiliation: Division of Nephrology and Hypertension and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Division of Nephrology and Hypertension and torres.vicente@mayo.edu.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
mesh_terms: D000818:Animals; D050034:Antidiuretic Agents / Q000008:administration & dosage; D065092:Antidiuretic Hormone Receptor Antagonists / Q000008:administration & dosage; D001552:Benzazepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000008:administration & dosage; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018895:Microsatellite Repeats / Q000235:genetics; D008957:Models, Genetic; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000235:genetics*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D050396:TRPP Cation Channels / Q000235:genetics*; D000077602:Tolvaptan
chemical_list: D050034:Antidiuretic Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000242:Cyclic AMP; D003894:Deamino Arginine Vasopressin; D013004:Somatostatin; D050396:TRPP Cation Channels; D000077602:Tolvaptan; C517782:pasireotide
keywords: cyclic AMP; polycystic kidney disease; somatostatin; vasopressin