Identification of SLC41A3 as a novel player in magnesium homeostasis.

Jeroen H.F De Baaij,Michiel Van Den Brand,René J.M Bindels,Marla Lavrijsen,Anke L.L Lameris,Joost G.J Hoenderop,Francisco J Arjona

doi:10.1038/srep28565

Abstract

Regulation of the body Mg2+ balance takes place in the distal convoluted tubule (DCT), where transcellular reabsorption determines the final urinary Mg2+ excretion. The basolateral Mg2+ extrusion mechanism in the DCT is still unknown, but recent findings suggest that SLC41 proteins contribute to Mg2+ extrusion. The aim of this study was, therefore, to characterize the functional role of SLC41A3 in Mg2+ homeostasis using the Slc41a3 knockout (Slc41a3−/−) mouse. By quantitative PCR analysis it was shown that Slc41a3 is the only SLC41 isoform with enriched expression in the DCT. Interestingly, serum and urine electrolyte determinations demonstrated that Slc41a3−/− mice suffer from hypomagnesemia. The intestinal Mg2+ absorption capacity was measured using the stable 25Mg2+ isotope in mice fed a low Mg2+ diet. 25Mg2+ uptake was similar in wildtype (Slc41a3+/+) and Slc41a3−/− mice, although Slc41a3−/− animals exhibited increased intestinal mRNA expression of Mg2+ transporters Trpm6 and Slc41a1. Remarkably, some of the Slc41a3−/− mice developed severe unilateral hydronephrosis. In conclusion, SLC41A3 was established as a new factor for Mg2+ handling.

Highlights

The aim of the present study was, to characterize the role of SLC41A3 in renal and intestinal Mg2+absorption
This study identified SLC41A3 as a novel player in Mg2+ homeostasis
This conclusion is based on the following results: i) Slc41a3 is expressed in the distal convoluted tubule (DCT) and in the intestine where Mg2+ isabsorbed; ii) Slc41a3−/− mice suffer from hypomagnesemia and normomagnesiuria indicating a possible renal Mg2+ leak; iii) intestinal Mg2+ transporters including Trpm[6] and Slc41a1 are upregulated in Slc41a3−/− mice

Summary

Introduction

The aim of the present study was, to characterize the role of SLC41A3 in renal and intestinal Mg2+ (re)absorption. For this purpose, Slc41a3 knockout mice (Slc41a3−/−) were analysed for electrolyte homeostasis, intestinal function and renal abnormalities. By challenging the mice with Mg2+-deficient diets, compensatory mechanisms in intestine, kidney and brain were examined in detail. Intestinal Mg2+ absorption studies were performed using the 25Mg2+ isotope to address the functional role of SLC41A3 in the intestine

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Conclusion