NaCl cotransporter activity and Mg2+handling by the distal convoluted tubule

Yujiro Maeoka, James A. McCormick

Research output: Contribution to journalReview articlepeer-review

Abstract

The genetic disease Gitelman syndrome, knockout mice, and pharmacological blockade with thiazide diuretics have revealed that reduced activity of the NaCl cotransporter (NCC) promotes renal Mg2+ wasting. NCC is expressed along the distal convoluted tubule (DCT), and its activity determines Mg2+ entry into DCT cells through transient receptor potential channel subfamily M member 6 (TRPM6). Several other genetic forms of hypomagnesemia lower the drive for Mg2+ entry by inhibiting activity of basolateral Na+-K+-ATPase, and reduced NCC activity may do the same. Lower intracellular Mg2+ may promote further Mg2+ loss by directly decreasing activity of Na+-K+-ATPase. Lower intracellular Mg2+ may also lower Na+-K+-ATPase indirectly by downregulating NCC. Lower NCC activity also induces atrophy of DCT cells, decreasing the available number of TRPM6 channels. Conversely, a mouse model with increased NCC activity was recently shown to display normal Mg2+ handling. Moreover, recent studies have identified calcineurin and uromodulin (UMOD) as regulators of both NCC and Mg2+ handling by the DCT. Calcineurin inhibitors paradoxically cause hypomagnesemia in a state of NCC activation, but this may be related to direct effects on TRPM6 gene expression. In Umod -/- mice, the cause of hypomagnesemia may be partly due to both decreased NCC expression and lower TRPM6 expression on the cell surface. This mini-review discusses these new findings and the possible role of altered Na+ flux through NCC and ultimately Na+-K+-ATPase in Mg2+ reabsorption by the DCT.

Original languageEnglish (US)
Pages (from-to)F1043-F1053
JournalAmerican Journal of Physiology - Renal Physiology
Volume319
Issue number6
DOIs
StatePublished - Nov 30 2020

Keywords

  • Calcineurin inhibitor
  • Magnesium
  • NaCl cotransporter
  • Transient receptor potential subfamily M member 6
  • Uromodulin

ASJC Scopus subject areas

  • Physiology
  • Urology

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