Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia

American Journal of Physiology. Renal Physiology
Mohammed Z FerdausJames McCormick

Abstract

Hypomagnesemia is associated with reduced kidney function and life-threatening complications and sustains hypokalemia. The distal convoluted tubule (DCT) determines final urinary Mg2+ excretion and, via activity of the Na+-Cl- cotransporter (NCC), also plays a key role in K+ homeostasis by metering Na+ delivery to distal segments. Little is known about the mechanisms by which plasma Mg2+ concentration regulates NCC activity and how low-plasma Mg2+ concentration and K+ concentration interact to modulate NCC activity. To address this, we performed dietary manipulation studies in mice. Compared with normal diet, abundances of total NCC and phosphorylated NCC (pNCC) were lower after short-term (3 days) or long-term (14 days) dietary Mg2+ restriction. Altered NCC activation is unlikely to play a role, since we also observed lower total NCC abundance in mice lacking the two NCC-activating kinases, STE20/SPS-1-related proline/alanine-rich kinase and oxidative stress response kinase-1, after Mg2+ restriction. The E3 ubiquitin-protein ligase NEDD4-2 regulates NCC abundance during dietary NaCl loading or K+ restriction. Mg2+ restriction did not lower total NCC abundance in inducible nephron-specific neuronal precursor cell developmentall...Continue Reading

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Citations

Oct 15, 2019·American Journal of Physiology. Renal Physiology·Alissa A FrameRichard D Wainford
Nov 3, 2020·American Journal of Physiology. Renal Physiology·Yujiro Maeoka, James A McCormick
Jul 1, 2020·Acta Physiologica·Gijs A C FrankenJeroen H F de Baaij
Feb 16, 2021·American Journal of Physiology. Renal Physiology·Catalina Sierra-RamosDiego Alvarez de la Rosa
Jun 27, 2021·The Journal of Biological Chemistry·Marleen L A KortenoevenRobert A Fenton

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Methods Mentioned

BETA
genotyping
PCR
PCRs
Fluorescence Imaging
blood draw

Software Mentioned

GraphPad Prism
ImageJ

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