title: Renoprotective effect of vasopressin v2 receptor antagonist tolvaptan in Dahl rats with end-stage heart failure.
abstract: Tolvaptan is a highly selective and orally effective arginine vasopressin V2 receptor antagonist, and is potentially useful for the treatment of heart failure (HF) patients. However, the renoprotective effect of long-term tolvaptan therapy and its underlying mechanisms remain unknown. We evaluated the effects of chronic treatment with tolvaptan on renal dysfunction, podocyte injury, inflammation, oxidative stress, Rho-kinase, epithelial-mesenchymal transition (EMT), and the extracellular signal-regulated protein kinase (ERK1/2) pathway in the renal cortex of Dahl salt-sensitive hypertensive (DS) rats with end-stage severe HF. DS and Dahl salt-resistant rats were fed a high-salt diet at 6 weeks of age. DS rats were treated with vehicle and tolvaptan (0.05% concentration in diet) from the age of 11 to 18 weeks. Vehicle-treated DS rats developed proteinuria, renal dysfunction, glomerulosclerosis, and interstitial fibrosis, which were ameliorated by tolvaptan without changing blood pressure. Decreased expression of nephrin and podocin and increased desmin-positive area in failing rats were restored by tolvaptan. Upregulation of NAD(P)H oxidase p22(phox), p47(phox), and gp91(phox), EMT markers such as transforming growth factor-β1, vimentin, and fibronectin expression, and Rho-kinase and ERK1/2 phosphorylation in DS rats were significantly suppressed by tolvaptan. Tolvaptan administration resulted in significant inhibition of tumor necrosis factor-α and monocyte chemoattractant protein-1 expression, and nuclear factor-κB phosphorylation. We concluded that long-term tolvaptan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with oxidative stress, as well as EMT, ERK, and the Rho-kinase pathway in the failing heart of DS rats. Thus, tolvaptan may be a therapeutic strategy for end-stage severe HF.
authors.affiliation: Department of Cardiology and Nephrology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.forename: Sho
authors.initials: S
authors.lastname: Onoda
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishimitsu
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009400:Nephrosclerosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D051381:Rats; D020303:Rats, Inbred Dahl; D013481:Superoxides / Q000378:metabolism; D000077602:Tolvaptan; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001552:Benzazepines; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019255:NADPH Oxidases; D016328:NF-kappa B; D013481:Superoxides; D000077602:Tolvaptan; D014409:Tumor Necrosis Factor-alpha; D054460:rho-Associated Kinases; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C491766:Ccl2 protein, rat