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

Wouter H Van Megen,Jenny Van Der Wijst,Paul R Grimm,Paul A Welling

doi:10.14814/phy2.13728

Abstract

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.

Highlights

Serum magnesium (Mg2+) levels are kept within physiological range through the combined effects of intestinal uptake, storage in bone and urinary excretion by the kidney
In concordance with a previous study (Grimm et al 2017), CA-Ste20p-related proline- and alaninerich kinase (SPAK) mice showed higher HCTZ-dependent Na+-reabsorption compared to their control littermates, as indicated by a higher Na+ excretion following HCTZ treatment (Fig. 2A)
An opposite effect was observed on the Mg2+ excretion of CA-SPAK mice (Fig. 2B)

Summary

Introduction

Serum magnesium (Mg2+) levels are kept within physiological range through the combined effects of intestinal uptake, storage in bone and urinary excretion by the kidney. The DCT reabsorbs Mg2+ from the pro-urine through the apically located Mg2+ channel transient receptor potential melastatin type 6 (TRMP6), which is regulated at the level of transcription, plasma membrane abundance and activity (van der Wijst et al 2014). In contrast to the well-known apical site of entry, the basolateral mechanism of Mg2+ extrusion in the DCT remains largely unknown. Several candidate transporters have been postulated, including cyclin M2 (CNNM2) (Stuiver et al 2011; Arjona et al 2014) as well as solute carrier family 41 member 1 (SLC41A1) (Kolisek et al 2012) and member 3 (SLC41A3) (de Baaij et al 2016), but especially the role of SLC41A3 and CNNM2 as basolateral Mg2+ transporters remains controversial (Mastrototaro et al 2016; Sponder et al 2016)

Methods

Results

Conclusion