Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6)

Mingzhu Nie, Manjot S. Bal, Jie Liu, Zhufeng Yang, Carolina Rivera, Xue Ru Wu, Joost G.J. Hoenderop, René J.M. Bindels, Denise K. Marciano, Matthias T.F. Wolf

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod/) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod/mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod/mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamindependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses.

Original languageEnglish (US)
Pages (from-to)16488-16502
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number42
DOIs
StatePublished - Jan 1 2018

Fingerprint

Uromodulin
Ion Channels
Magnesium
Homeostasis
Kidney
Nutrition
Endocytosis
Up-Regulation
Extremities
Diet
Biotinylation
Transient Receptor Potential Channels
Furosemide
Clamping devices
Extracellular Space
Medical problems
Chronic Renal Insufficiency
Diuretics
Knockout Mice
Type 2 Diabetes Mellitus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6). / Nie, Mingzhu; Bal, Manjot S.; Liu, Jie; Yang, Zhufeng; Rivera, Carolina; Wu, Xue Ru; Hoenderop, Joost G.J.; Bindels, René J.M.; Marciano, Denise K.; Wolf, Matthias T.F.

In: Journal of Biological Chemistry, Vol. 293, No. 42, 01.01.2018, p. 16488-16502.

Research output: Contribution to journalArticle

Nie, Mingzhu ; Bal, Manjot S. ; Liu, Jie ; Yang, Zhufeng ; Rivera, Carolina ; Wu, Xue Ru ; Hoenderop, Joost G.J. ; Bindels, René J.M. ; Marciano, Denise K. ; Wolf, Matthias T.F. / Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6). In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 42. pp. 16488-16502.
@article{84b67cf974164591bb759fdf60dba784,
title = "Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6)",
abstract = "Up to 15{\%} of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod/) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod/mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod/mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamindependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses.",
author = "Mingzhu Nie and Bal, {Manjot S.} and Jie Liu and Zhufeng Yang and Carolina Rivera and Wu, {Xue Ru} and Hoenderop, {Joost G.J.} and Bindels, {Ren{\'e} J.M.} and Marciano, {Denise K.} and Wolf, {Matthias T.F.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA118.003950",
language = "English (US)",
volume = "293",
pages = "16488--16502",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6)

AU - Nie, Mingzhu

AU - Bal, Manjot S.

AU - Liu, Jie

AU - Yang, Zhufeng

AU - Rivera, Carolina

AU - Wu, Xue Ru

AU - Hoenderop, Joost G.J.

AU - Bindels, René J.M.

AU - Marciano, Denise K.

AU - Wolf, Matthias T.F.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod/) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod/mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod/mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamindependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses.

AB - Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod/) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod/mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod/mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamindependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses.

UR - http://www.scopus.com/inward/record.url?scp=85055072500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055072500&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.003950

DO - 10.1074/jbc.RA118.003950

M3 - Article

VL - 293

SP - 16488

EP - 16502

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -