TY - JOUR
T1 - Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats
AU - Wang, Anyi
AU - Hirose, Takuo
AU - Ohsaki, Yusuke
AU - Takahashi, Chika
AU - Sato, Emiko
AU - Oba-Yabana, Ikuko
AU - Kinugasa, Satoshi
AU - Muroya, Yoshikazu
AU - Ito, Sadayoshi
AU - Mori, Takefumi
N1 - Funding Information:
Conflict of interest T.M. and S.I. are consultants for a clinical trial being conducted by Otsuka Pharmaceutical. T.M. has also received honoraria for lectures and research funding from Otsuka Pharmaceutical. The Division of Integrative Renal Replacement Therapy is financially supported by Terumo, JMS, Kyowa Hakko Kirin, and Otsuka Pharmaceutical.
Funding Information:
The authors are grateful to the Biomedical Research Unit of Tohoku University Hospital and the Institute for Animal Experimentation Tohoku University Graduate School of Medicine as well as the Center of Research Instruments, Institute of Development, Aging and Cancer (IDAC), Tohoku University for the use of their equipment. We thank Ms. Yayoi Aoyama for technical assistance. This study was supported in part by Grants for Scientific Research (Japan Society for the Promotion of Science; 23659438, 25860156, 26670424, 15K18694, 15H04834, and 16H05312) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT).
Funding Information:
Research Unit of Tohoku University Hospital and the Institute for Animal Experimentation Tohoku University Graduate School of Medicine as well as the Center of Research Instruments, Institute of Development, Aging and Cancer (IDAC), Tohoku University for the use of their equipment. We thank Ms. Yayoi Aoyama for technical assistance. This study was supported in part by Grants for Scientific Research (Japan Society for the Promotion of Science; 23659438, 25860156, 26670424, 15K18694, 15H04834, and 16H05312) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT).
Publisher Copyright:
© 2018, Japanese Society of Nephrology.
PY - 2019/4/2
Y1 - 2019/4/2
N2 - 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.
AB - 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.
KW - Antidiuretics
KW - Diabetes insipidus
KW - Glomerular filtration rate
KW - V2 receptor antagonist
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U2 - 10.1007/s10157-018-1669-9
DO - 10.1007/s10157-018-1669-9
M3 - Article
C2 - 30426292
AN - SCOPUS:85056482898
VL - 23
SP - 455
EP - 464
JO - Clinical and Experimental Nephrology
JF - Clinical and Experimental Nephrology
SN - 1342-1751
IS - 4
ER -