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Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH

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Abstract

Background

Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model.

Methods

Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9). The rats were sacrificed to obtain kidney tissues 3 days after treatment. In addition to electrolyte metabolism, changes in expressions of the urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2 and NPT1 (SLC17A1) were examined by western blotting and immunohistochemistry.

Results

In the terlipressin-treated rats, serum uric acid (UA) significantly decreased and the excretion of urinary UA significantly increased, resulting in marked increase in fractional excretion of UA. Although no change in the expression of URAT1, GLUT9 expression significantly decreased whereas the expressions of ABCG2 and NPT1 significantly increased in the terlipressin group. The results of immunohistochemistry corroborated with those of the western blotting. Aquaporin 2 expression did not change in the medulla, suggesting the independence of V2 receptor stimulation.

Conclusion

Stimulation of V1a receptor induces the downregulation of GLUT9, reabsorption urate transporter, together with the upregulation of ABCG2 and NPT1, secretion urate transporters, all changes of which clearly lead to increase in renal UA clearance. Hypouricemia seen in SIADH is attributable to V1a receptor stimulation.

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Acknowledgments

We thank all the doctors in the Division of Nephrology, the Department of Internal Medicine, Teikyo University School of Medicine for their continued cooperation. We are especially indebted to Ms. Hiromi Yamaguchi and Ms. Miyuki Fukazawa for their excellent technical assistance. We also thank Dr. Makoto Hosoyamada, MD, PhD, Human Physiology and Pathology, Faculty of Pharma Sciences, Teikyo University, Tokyo. Japan, for discussing on the uric acid measurement and Dr. Hirotaka Matsuo MD, PhD, Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan, for discussing on the antibody for urate transporters. This study was supported in part by a Grant-in-Aid for Progressive Renal Diseases Research, Research on Rare and Intractable Disease, from the Ministry of Health, Labour and Welfare of Japan (to SU) and Gout Research Foundation (to SU).

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Authors and Affiliations

  1. Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Kei Taniguchi, Yoshifuru Tamura, Takanori Kumagai, Shigeru Shibata & Shunya Uchida

  2. Support for Community Medicine Endowed Chair, Teikyo University School of Medicine, Tokyo, Japan

    Takanori Kumagai

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  1. Kei Taniguchi
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  2. Yoshifuru Tamura
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  3. Takanori Kumagai
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  4. Shigeru Shibata
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  5. Shunya Uchida
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Correspondence to Shunya Uchida.

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Taniguchi, K., Tamura, Y., Kumagai, T. et al. Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH. Clin Exp Nephrol 20, 845–852 (2016). https://doi.org/10.1007/s10157-016-1248-x

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  • DOI: https://doi.org/10.1007/s10157-016-1248-x

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