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.

Keywords: Gordon syndrome; kidney; magnesium; sodium.