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

Active reabsorption of magnesium (Mg ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg 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 Mg balance. To further elucidate the possible interrelationship between NCC activity and renal Mg handling, plasma Mg levels and urinary excretion of sodium (Na ) and Mg 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 Mg 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 Mg reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA-SPAK mice exhibited higher urinary Mg excretion, while urinary Na excretion decreased to levels observed in control animals. Surprisingly, CA-SPAK mice had unaltered renal expression of Trpm6, encoding the Mg -permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA-SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na reabsorption. Thus, Mg 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 Mg excretion after prolonged HCTZ administration.