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

Mohammed Z. Ferdaus, Anindit Mukherjee, Jonathan W. Nelson, Philip J. Blatt, Lauren N. Miller, Andrew S. Terker, Olivier Staub, Dao Hong Lin, James A. McCormick

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg2+ or combined Mg2+-K+ restriction but were dramatically lower compared with a low-K+ diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na+ delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg2+-K+ restriction, but, surprisingly, NCC was not activated after long-term K+ restriction despite lower plasma K+ concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K+ restriction.

Original languageEnglish (US)
Pages (from-to)F825-F838
JournalAmerican journal of physiology. Renal physiology
Volume317
Issue number4
DOIs
StatePublished - Oct 1 2019

Fingerprint

Member 3 Solute Carrier Family 12
Hypokalemia
Down-Regulation
Phosphotransferases
Diet
Ubiquitin-Protein Ligases
Nephrons

Keywords

  • magnesium
  • Na+-Cl− cotransporter
  • potassium
  • transport

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia. / Ferdaus, Mohammed Z.; Mukherjee, Anindit; Nelson, Jonathan W.; Blatt, Philip J.; Miller, Lauren N.; Terker, Andrew S.; Staub, Olivier; Lin, Dao Hong; McCormick, James A.

In: American journal of physiology. Renal physiology, Vol. 317, No. 4, 01.10.2019, p. F825-F838.

Research output: Contribution to journalArticle

Ferdaus, MZ, Mukherjee, A, Nelson, JW, Blatt, PJ, Miller, LN, Terker, AS, Staub, O, Lin, DH & McCormick, JA 2019, 'Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia', American journal of physiology. Renal physiology, vol. 317, no. 4, pp. F825-F838. https://doi.org/10.1152/ajprenal.00216.2019
Ferdaus, Mohammed Z. ; Mukherjee, Anindit ; Nelson, Jonathan W. ; Blatt, Philip J. ; Miller, Lauren N. ; Terker, Andrew S. ; Staub, Olivier ; Lin, Dao Hong ; McCormick, James A. / Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia. In: American journal of physiology. Renal physiology. 2019 ; Vol. 317, No. 4. pp. F825-F838.
@article{84cb949ac2b54b37bf132c2a4011a289,
title = "Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia",
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 developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg2+ or combined Mg2+-K+ restriction but were dramatically lower compared with a low-K+ diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na+ delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg2+-K+ restriction, but, surprisingly, NCC was not activated after long-term K+ restriction despite lower plasma K+ concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K+ restriction.",
keywords = "magnesium, Na+-Cl− cotransporter, potassium, transport",
author = "Ferdaus, {Mohammed Z.} and Anindit Mukherjee and Nelson, {Jonathan W.} and Blatt, {Philip J.} and Miller, {Lauren N.} and Terker, {Andrew S.} and Olivier Staub and Lin, {Dao Hong} and McCormick, {James A.}",
year = "2019",
month = "10",
day = "1",
doi = "10.1152/ajprenal.00216.2019",
language = "English (US)",
volume = "317",
pages = "F825--F838",
journal = "American journal of physiology. Renal physiology",
issn = "0363-6127",
number = "4",

}

TY - JOUR

T1 - Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia

AU - Ferdaus, Mohammed Z.

AU - Mukherjee, Anindit

AU - Nelson, Jonathan W.

AU - Blatt, Philip J.

AU - Miller, Lauren N.

AU - Terker, Andrew S.

AU - Staub, Olivier

AU - Lin, Dao Hong

AU - McCormick, James A.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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 developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg2+ or combined Mg2+-K+ restriction but were dramatically lower compared with a low-K+ diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na+ delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg2+-K+ restriction, but, surprisingly, NCC was not activated after long-term K+ restriction despite lower plasma K+ concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K+ restriction.

AB - 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 developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg2+ or combined Mg2+-K+ restriction but were dramatically lower compared with a low-K+ diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na+ delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg2+-K+ restriction, but, surprisingly, NCC was not activated after long-term K+ restriction despite lower plasma K+ concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K+ restriction.

KW - magnesium

KW - Na+-Cl− cotransporter

KW - potassium

KW - transport

UR - http://www.scopus.com/inward/record.url?scp=85072351103&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072351103&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00216.2019

DO - 10.1152/ajprenal.00216.2019

M3 - Article

C2 - 31364380

AN - SCOPUS:85072351103

VL - 317

SP - F825-F838

JO - American journal of physiology. Renal physiology

JF - American journal of physiology. Renal physiology

SN - 0363-6127

IS - 4

ER -