SLC41A1 knockout mice display normal magnesium homeostasis

Transcellular Mg²⁺ reabsorption in the distal convoluted tubule (DCT) of the kidneys plays an important role in maintaining systemic Mg²⁺ homeostasis. SLC41A1 is a Na⁺/Mg²⁺ exchanger that mediates Mg²⁺ efflux from cells and is hypothesized to facilitate basolateral extrusion of Mg²⁺ in the DCT. In this study, we generated a SLC41A1 knockout mouse model to examine the role of SLC41A1 in Mg²⁺ homeostasis. Slc41a1 mice exhibited similar serum and urine Mg²⁺ levels as their wild-type littermates. Dietary restriction of Mg²⁺ resulted in reduced serum Mg²⁺ concentration and urinary Mg²⁺ excretion, which was similar in the wild-type and knockout groups. Expression of genes encoding Mg²⁺ channels and transporters such as transient receptor potential melastatin 6 (Trpm6), transient receptor potential melastatin 7 (Trpm7), cyclin and CBS domain divalent metal cation transport mediator 2 (Cnnm2), and Slc41a3 were unchanged based on genotype. We investigated the potential redundancy of SLC41A1 and its homolog SLC41A3 by generating a double knockout mouse. Although Slc41a3 knockout mice showed significantly reduced serum Mg²⁺ compared with wild-type and Slc41a1 knockout groups, double knockout mice displayed similar serum Mg²⁺ levels as Slc41a3 knockout mice. In conclusion, our data show that SLC41A1 is not involved in the regulation of systemic Mg²⁺ homeostasis in mice. Our data also demonstrate that SLC41A1 does not compensate for the loss of SLC41A3, suggesting different functions of these SLC41 proteins in vivo.NEW & NOTEWORTHY SLC41A1 has been hypothesized to mediate Mg²⁺ extrusion in the distal convoluted tubule and thus regulate Mg²⁺ homeostasis. This study investigated the role of SLC41A1 in Mg²⁺ homeostasis in vivo using a transgenic mouse model. Our results demonstrate that SLC41A1 is not required to maintain normal Mg²⁺ balance in mice. We also show that SLC41A3 is more important than SLC41A1 in regulating systemic Mg²⁺ levels.