Mg<sup>2+</sup> restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia.

Détails

ID Serval
serval:BIB_A3B2541B62F6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mg<sup>2+</sup> restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia.
Périodique
American journal of physiology. Renal physiology
Auteur(s)
Ferdaus M.Z., Mukherjee A., Nelson J.W., Blatt P.J., Miller L.N., Terker A.S., Staub O., Lin D.H., McCormick J.A.
ISSN
1522-1466 (Electronic)
ISSN-L
1522-1466
Statut éditorial
Publié
Date de publication
01/10/2019
Peer-reviewed
Oui
Volume
317
Numéro
4
Pages
F825-F838
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Hypomagnesemia is associated with reduced kidney function and life-threatening complications and sustains hypokalemia. The distal convoluted tubule (DCT) determines final urinary Mg <sup>2+</sup> excretion and, via activity of the Na <sup>+</sup> -Cl <sup>-</sup> cotransporter (NCC), also plays a key role in K <sup>+</sup> homeostasis by metering Na <sup>+</sup> delivery to distal segments. Little is known about the mechanisms by which plasma Mg <sup>2+</sup> concentration regulates NCC activity and how low-plasma Mg <sup>2+</sup> concentration and K <sup>+</sup> 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 Mg <sup>2+</sup> 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 Mg <sup>2+</sup> restriction. The E3 ubiquitin-protein ligase NEDD4-2 regulates NCC abundance during dietary NaCl loading or K <sup>+</sup> restriction. Mg <sup>2+</sup> restriction did not lower total NCC abundance in inducible nephron-specific neuronal precursor cell developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg <sup>2+</sup> or combined Mg <sup>2+</sup> -K <sup>+</sup> restriction but were dramatically lower compared with a low-K <sup>+</sup> diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na <sup>+</sup> delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg <sup>2+</sup> -K <sup>+</sup> restriction, but, surprisingly, NCC was not activated after long-term K <sup>+</sup> restriction despite lower plasma K <sup>+</sup> concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K <sup>+</sup> restriction.
Mots-clé
magnesium, potassium, sodium chloride cotransporter, transport, Na+-Cl− cotransporter
Pubmed
Web of science
Création de la notice
06/08/2019 16:13
Dernière modification de la notice
28/10/2019 6:09
Données d'usage