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Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats

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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.

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Acknowledgements

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).

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Authors and Affiliations

  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

    Anyi Wang, Emiko Sato & Sadayoshi Ito

  2. Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan

    Takuo Hirose, Ikuko Oba-Yabana, Satoshi Kinugasa, Yoshikazu Muroya & Takefumi Mori

  3. Division of Integrated Renal Replacement Therapy, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan

    Yusuke Ohsaki, Chika Takahashi & Takefumi Mori

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  1. Anyi Wang
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Contributions

AW, TH, and TM designed the study and wrote the initial draft of the manuscript. TM and SI supervised the project. AW, YO, and CT performed the animal experiments. AW, TH, CT, ES, IO-Y, SK, and YM contributed to the analysis and interpretation of data. All authors critically reviewed the manuscript and approved the final version.

Corresponding author

Correspondence to Takefumi Mori.

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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.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (IRB approval number: 2015MdA-085 and 2016MdA-177).

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Wang, A., Hirose, T., Ohsaki, Y. et al. Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats. Clin Exp Nephrol 23, 455–464 (2019). https://doi.org/10.1007/s10157-018-1669-9

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  • DOI: https://doi.org/10.1007/s10157-018-1669-9

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