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The Epithelial Mg²⁺ Channel Transient Receptor Potential Melastatin 6 Is Regulated by Dietary Mg²⁺ Content and Estrogens

Wouter M. Tiel Groenestege^*, Joost G. Hoenderop^*, Lambertus van den Heuvel, Nine Knoers and René J. Bindels^*

Departments of ^* Physiology, Pediatrics, and Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Address correspondence to: Dr. René J.M. Bindels, Radboud University Nijmegen Medical Centre, 286 Cell Physiology, PO Box 9101, Nijmegen 6500 HB, The Netherlands. Phone: +31-24-3614211; Fax: +31-24-3616413; E-mail: r.bindels{at}ncmls.ru.nl

Received for publication July 10, 2005. Accepted for publication January 20, 2006.

The kidney is the principal organ responsible for the regulation of the body Mg²⁺ balance. Identification of the gene defect in hypomagnesemia with secondary hypocalcemia recently elucidated transient receptor potential melastatin 6 (TRPM6) as the gatekeeper in transepithelial Mg²⁺ transport, whereas its homolog, TRPM7, is implicated in cellular Mg²⁺ homeostasis. The aim of this study was to determine the tissue distribution in mouse and regulation of TRPM6 and TRPM7 by dietary Mg²⁺ and hormones. This study demonstrates that TRPM6 is expressed predominantly in kidney, lung, cecum, and colon, whereas TRPM7 is distributed ubiquitously. Dietary Mg²⁺ restriction in mice resulted in hypomagnesemia and renal Mg²⁺ and Ca²⁺ conservation, whereas a Mg²⁺-enriched diet led to increased urinary Mg²⁺ and Ca²⁺ excretion. Conversely, Mg²⁺ restriction significantly upregulated renal TRPM6 mRNA levels, whereas a Mg²⁺ enriched diet increased TRPM6 mRNA expression in colon. Dietary Mg²⁺ did not alter TRPM7 mRNA expression in mouse kidney and colon. In addition, it was demonstrated that 17-estradiol but not 1,25-dihydroxyvitamin D₃ or parathyroid hormone regulates TRPM6 renal mRNA levels. Renal TRPM7 mRNA abundance remained unaltered under these conditions. The renal TRPM6 mRNA level in ovariectomized rats was significantly reduced, whereas 17-estradiol treatment normalized TRPM6 mRNA levels. In conclusion, kidney, lung, cecum, and colon likely constitute the main sites of active Mg²⁺ (re)absorption in the mouse. In addition, Mg²⁺ restriction and 17-estradiol upregulated renal TRPM6 mRNA levels, whereas a Mg²⁺-enriched diet stimulated TRPM6 mRNA expression in colon, supporting the gatekeeper function of TRPM6 in transepithelial Mg²⁺ transport.

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