Renoprotective Effect of Vasopressin V2 Receptor Antagonist Tolvaptan in Dahl Rats With End-Stage Heart Failure
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概要
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Tolvaptan is a highly selective and orally effective arginine vasopressin V<SUB>2</SUB> 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<SUP>phox</SUP>, p47<SUP>phox</SUP>, and gp91<SUP>phox</SUP>, EMT markers such as transforming growth factor-<I>β</I>1, 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-<I>α</I> and monocyte chemoattractant protein-1 expression, and nuclear factor-<I>κ</I>B 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.
著者
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Ishimitsu Toshihiko
Department Of Hypertension And Cardiorenal Medicine Dokkyo Medical University
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Ishikawa Mayuko
Department Of Hypertension And Cardiorenal Medicine Dokkyo Medical University School Of Medicine
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Sugiyama Fumihiro
Department of Cardiology and Nephrology, Dokkyo Medical University School of Medicine
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Kobayashi Naohiko
Department of Cardiology and Nephrology, Dokkyo Medical University School of Medicine
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Onoda Sho
Department of Cardiology and Nephrology, Dokkyo Medical University School of Medicine
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Ishikawa Mayuko
Department of Cardiology and Nephrology, Dokkyo Medical University School of Medicine
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