Renal claudin-14 expression is not required for regulating magnesium balance in mice
The kidneys play a crucial role in maintaining calcium (Ca2+) and magnesium (Mg2+) homeostasis by regulating these minerals' reabsorption. In the thick ascending limb of Henle's loop (TAL), Ca2+ and Mg2+ are reabsorbed through the tight junctions by a shared paracellular pathway formed by claudin-16 and claudin-19. Hypercalcemia activates the Ca2+-sensing receptor (CaSR) in the TAL, causing upregulation of the pore-blocking claudin-14 (CLDN14) that reduces Ca2+ and Mg2+ reabsorption from this segment. Additionally, a high Mg2+ diet is known to increase both urinary Mg2+ and Ca2+ excretion. Since Mg2+ may also activate the CaSR, we aimed to investigate whether CaSR-dependent increases in CLDN14 expression also regulate urinary Mg2+ excretion in response to hypermagnesemia. Here we show that a Mg2+-enriched diet increased urinary Mg2+ and Ca2+ excretion in mice, however this occurred without detectable changes in renal CLDN14 expression. The administration of a high Mg2+ diet to Cldn14-/- mice did not cause more pronounced hypermagnesemia nor significantly alter urinary Mg2+ excretion. Finally, in vitro evaluation of CaSR-driven Cldn14 promoter activity in response to increasing Mg2+ concentrations revealed that Cldn14 expression only increases at supraphysiological extracellular Mg2+ levels. Together, these results suggest that CLDN14 is not involved in regulating extracellular Mg2+ balance following high dietary Mg2+ intake.