Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome.

Abstract

Active reabsorption of magnesium (Mg2+ ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg2+ homeostasis. Impaired activity of the Na+ -Cl- -cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg2+ balance. To further elucidate the possible interrelationship between NCC activity and renal Mg2+ handling, plasma Mg2+ levels and urinary excretion of sodium (Na+ ) and Mg2+ were measured in a mouse model of Gordon syndrome. In this model, DCT1-specific expression of a constitutively active mutant form of the NCC-phosphorylating kinase, SPAK (CA-SPAK), increases NCC activity and hydrochlorothiazide (HCTZ)-sensitive Na+ reabsorption. These mice were normomagnesemic and HCTZ administration comparably reduced plasma Mg2+ levels in CA-SPAK mice and control littermates. As inferred by the initial response to HCTZ, CA-SPAK mice exhibited greater NCC-dependent Na+ reabsorption together with decreased Mg2+ reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA-SPAK mice exhibited higher urinary Mg2+ excretion, while urinary Na+ excretion decreased to levels observed in control animals. Surprisingly, CA-SPAK mice had unaltered renal expression of Trpm6, encoding the Mg2+ -permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA-SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na+ reabsorption. Thus, Mg2+ reabsorption is not coupled to increased thiazide-sensitive Na+ reabsorption, suggesting a similar process explains normomagnesemia in Gordon syndrome. Further research is required to unravel the molecular underpinnings of this phenomenon and the more pronounced Mg2+ excretion after prolonged HCTZ administration.

• Authors: Wouter H van Megen, Paul R Grimm, Paul A Welling, Jenny van der Wijst
• Journal: Physiological reports (Physiol Rep) Vol. 6 Issue 14 Pg. e13728 (07 2018) ISSN: 2051-817X [Electronic] United States
• PMID: 30030908 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Cation Transport Proteins
• Slc12a3 protein, mouse
• Sodium Chloride Symporter Inhibitors
• Solute Carrier Family 12, Member 3
• TRPM Cation Channels
• Trpm6 protein, mouse
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
• Hydrochlorothiazide
• Sodium
• Stk39 protein, mouse
• Protein Serine-Threonine Kinases
• Magnesium

Topics

• Animals
• Arthrogryposis (metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Cleft Palate (metabolism)
• Clubfoot (metabolism)
• Female
• Hand Deformities, Congenital (metabolism)
• Hydrochlorothiazide (pharmacology)
• Kidney (drug effects, metabolism)
• Magnesium (metabolism)
• Male
• Mice
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Renal Reabsorption
• Sodium (metabolism)
• Sodium Chloride Symporter Inhibitors (pharmacology)
• Solute Carrier Family 12, Member 3 (genetics, metabolism)
• TRPM Cation Channels (genetics, metabolism)