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.