Background/Aims: Renal tubular Mg2+ reabsorption is mediated predominantly by the tight junction channel protein claudin-16 which is encoded by the gene CLDN16. Hypermagnesemia decreases, whereas hypomagnesemia increases Mg2+ reabsorption. This study examines the role of claudin-16 in the adaptive response of the kidney to Mg2+ availability. Methods/Results: Mice received a low-, normal- or high Mg2+ diet for up to 3 days. Mg2+-loaded animals displayed hypermagnesemia with increasing urine Mg2+/Ca2+ levels paralleled by a decrease in claudin-16 protein and mRNA in the kidney. Mg2+- deprived animals developed hypomagnesemia with decreasing urine Mg2+/Ca2+ levels associated with an increase in claudin-16 protein and mRNA abundance. Mg2+ depletion markedly increased and Mg2+ load decreased endogenous claudin-16 mRNA levels in calcium-sensing receptor-transfected HEK293 cells compared with native HEK293 cells. The effect of Mg2+ availability on the human CLDN16 (hCLDN16) gene promoter was examined. Using a 2.5kb hCLDN16 5′-flanking DNA sequence, we show that magnesium depletion increases and Mg2+ load decreases hCLDN16 promoter activity in transfected HEK293 cells. Conclusions: Changes in Mg2+ availability may influence claudin-16 mediated Mg2+ transport at the transcriptional level. The possible involvement of the cell membrane bound Ca2+/Mg2+ sensing receptor or the potential role of a hypothetical Mg2+ response element on the CLDN16 promoter in the Mg2+-induced response remains to be explored.

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