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

Active reabsorption of magnesium (Mg(2+)) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg(2+) 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(2+) balance. To further elucidate the possible interrelationship between NCC activity and renal Mg(2+) handling, plasma Mg(2+) levels and urinary excretion of sodium (Na(+)) and Mg(2+) 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(2+) 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(2+) reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA‐SPAK mice exhibited higher urinary Mg(2+) 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(2+)‐permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA‐SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na(+) reabsorption. Thus, Mg(2+) 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(2+) excretion after prolonged HCTZ administration.