4.5 Article

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

Journal

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 320, Issue 5, Pages F897-F907

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00590.2020

Keywords

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

Funding

  1. Canadian Institutes of Health Research
  2. Fabrikant Vilhelm Pedersen og Hustrus Mindelegat
  3. Novo Nordisk Foundation
  4. Beckett Foundation
  5. Carlsberg Foundation
  6. Independent Research Fund Denmark
  7. Erasmusthorn [2018/Ethorn/4458087]

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This study investigated the role of Mg2+ in regulating urinary excretion of Ca2+ and Mg2+ through the Ca2+-sensing receptor-claudin 14 (CLDN14) pathway using transgenic models and in vitro assays. The results suggest that CLDN14 is unlikely to play a significant role in the compensatory response to hypermagnesemia.
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.

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