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

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