Renal claudin-14 expression is not required for regulating Mg2+ balance in mice

Abstract

The kidneys play a crucial role in maintaining Ca²⁺ and 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 pore-blocking claudin-14 (CLDN14), which reduces Ca²⁺ and Mg²⁺ reabsorption from this segment. In addition, a high-Mg²⁺ diet is known to increase both urinary Mg²⁺ and Ca²⁺ excretion. Since Mg²⁺ may also activate 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 or 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.NEW & NOTEWORTHY Using transgenic models and in vitro assays, this study examined the effect of Mg²⁺ on regulating urinary excretion of Ca²⁺ and Mg²⁺ via activation of the Ca²⁺-sensing receptor-claudin 14 (CLDN14) pathway. The study suggests that CLDN14 is unlikely to play a significant role in the compensatory response to hypermagnesemia.

Keywords: Ca2+-sensing receptor; claudin-14; kidney; magnesium; tight junctions.