Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome
PublisherAmerican Physiological Society
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AbstractActive 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. Copyright 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
SponsorsWHM is supported by the Dutch Kidney Foundation Kolff fellowship abroad grant (16OKK61). JW is supported by the European Union's Horizon 2020 Marie Sk?odowska-Curie (grant agreement No 748058) and by The Netherlands Organisation for Health Research and Development (Off Road grant 451001 004). The work was performed in the laboratory of PAW and supported by funds from the NIDDK, DK054231 DK093501.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85050795814&doi=10.14814%2fphy2.13728&partnerID=40&md5=3de14cf8f4bc18977c8b06e4e769d77c; http://hdl.handle.net/10713/8929
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