title: Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury.
abstract: Tolvaptan, a selective vasopressin V2 receptor antagonist, slows the increase in total kidney volume and the decline in kidney function in patients with the results of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Outcome (TEMPO) 3:4 trial. However, it was unclear which dose of tolvaptan was optimal or whether tolvaptan was able to delay progression to end-stage renal disease (ESRD). Here we examined the relationship with aquaresis and the inhibitory effect on cyst development in short-term treatment and mortality as an index of ESRD in long-term treatment with tolvaptan using DBA/2FG-pcy mice, an animal model of nephronophthisis. With short-term treatment from 5 to 15 weeks of age, tolvaptan (0.01-0.3% via diet) dose-dependently enhanced aquaresis, prevented increases in kidney weight and cyst volume, and was associated with significant reductions in kidney cAMP levels and extracellular signal-regulated kinase activity. Maximal effects of tolvaptan on aquaresis and the prevention of development of polycystic kidney disease (PKD) were obtained at 0.1%. Interestingly, tolvaptan also dose-dependently reduced urinary neutrophil gelatinase-associated lipocalin levels in correlation with the kidney volume. With long-term treatment from 5 to 29 weeks of age, tolvaptan significantly attenuated the increase in kidney volume by up to 50% and reduced urinary albumin excretion. Furthermore, tolvaptan significantly reduced the mortality rate to 20%, compared with 60% in the control group. These data indicate that tolvaptan may delay the onset of ESRD in PKD by suppressing the increases in kidney volume and renal injury, providing a promising treatment for PKD.
authors.affiliation: First Institute of New Drug Discovery (M.A., H.F., H.M., K.H., K.O., K.N.) and Laboratory of Bioenergetics Research, Tokushima Research Institute (M.I.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan; and Global Pharmaceutical Business, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan (Y.Y.).
authors.forename: Miki
authors.initials: M
authors.lastname: Aihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Katsuji
authors.initials: K
authors.lastname: Hattori
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagano
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamamura
mesh_terms: D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000652:urine; D009929:Organ Size; D007690:Polycystic Kidney Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D013997:Time Factors; D000077602:Tolvaptan
chemical_list: D000209:Acute-Phase Proteins; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse; D000077602:Tolvaptan; D000242:Cyclic AMP