Anyi Wang1, Takuo Hirose2, Yusuke Ohsaki3, Chika Takahashi3, Emiko Sato1, Ikuko Oba-Yabana2, Satoshi Kinugasa2, Yoshikazu Muroya2, Sadayoshi Ito1, Takefumi Mori4,5. 1. Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan. 2. Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan. 3. Division of Integrated Renal Replacement Therapy, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan. 4. Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan. tmori@tohoku-mpu.ac.jp. 5. Division of Integrated Renal Replacement Therapy, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan. tmori@tohoku-mpu.ac.jp.
Abstract
BACKGROUND: Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. METHODS: Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. RESULTS: Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. CONCLUSION: HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.
BACKGROUND:Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. METHODS: Male PCKrats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. RESULTS: Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. CONCLUSION:HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.
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