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Down-regulation of TRPM6-mediated magnesium influx by cyclosporin A

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Abstract

Transient receptor potential melastatin 6 (TRPM6) is distributed along the apical membrane of the renal tubular cells and is involved in the reabsorption of magnesium. In this study, we show that TRPM6 expression is suppressed by cyclosporin A (CsA) via a down-regulation of c-Fos expression. TRPM6 was expressed in NRK-52E, but not in Madin-Darby canine kidney cells. In contrast, its homolog, TRPM7, was equally expressed in both cells. In NRK-52E cells, CsA dose-dependently decreased TRPM6 expression without affecting TRPM7 expression. Magnesium load measurements revealed the rise in the intracellular free magnesium concentration ([Mg2+]i) to be inhibited by CsA. The transfection of TRPM6 siRNA decreased TRPM6 expression without affecting TRPM7 expression and inhibited the elevation of [Mg2+]i. CsA did not affect the intracellular distribution of nuclear factor of activated T cells (NFATc). Furthermore, TRPM6 expression was not changed by a NFATc inhibitor. Next, we examined the effect of CsA on the transcription factors c-Fos and c-Jun. CsA decreased c-Fos expression without affecting c-Jun expression. The transfection of c-Fos siRNA suppressed TRPM6 expression without affecting TRPM7 expression. We suggest that CsA decreases TRPM6 expression mediated by inhibition of c-Fos transcription, resulting in a decrease of renal Mg2+ reabsorption.

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Abbreviations

CsA:

cyclosporin A

NFATc:

nuclear factor of activated T cells

[Mg2+]i :

intracellular free magnesium concentration

TRPM6:

transient receptor potential melastatin 6

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Acknowledgements

This work was supported in part by the Ministry of Education, Science, Sports, and Culture of Japan, a grant-in-aid for Encouragement of Young Scientists (to A.I.), and by grants from the Ichiro Kanehara Foundation, the Salt Science Research Foundation, no. 0633, and the SRI academic Research Grant (to A.I.). Akira Ikari and Chiaki Okude contributed equally to this work.

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Authors and Affiliations

  1. Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Akira Ikari, Chiaki Okude, Hayato Sawada, Tadanobu Takahashi, Junko Sugatani & Masao Miwa

  2. COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Junko Sugatani

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  1. Akira Ikari
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Correspondence to Akira Ikari.

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Ikari, A., Okude, C., Sawada, H. et al. Down-regulation of TRPM6-mediated magnesium influx by cyclosporin A. Naunyn-Schmied Arch Pharmacol 377, 333–343 (2008). https://doi.org/10.1007/s00210-007-0212-4

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