Kidney Week

Abstract: SA-PO1029

SLC41A1 Mediates Magnesium Reabsorption in the Kidney

Session Information

• Fluid and Electrolytes: Basic - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Hoenderop, Joost, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, Netherlands

Joost Hoenderop,

• Arjona, Francisco J., Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, Netherlands

Francisco J. Arjona,

• Bindels, René J., Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, Netherlands

René J. Bindels,

• De Baaij, Jeroen H.F., Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, Netherlands

Jeroen H.F. De Baaij,

Background

Solute carrier family 41 member A1 (SLC41A1) has been suggested to mediate magnesium (Mg²⁺) transport and to maintain Mg²⁺ homeostasis in humans. However, the function of SLC41A1 in the kidney, the main organ maintaining Mg²⁺ homeostasis, remains to be elucidated.

Methods

In this study, cellular Mg²⁺ transport assays combined with zebrafish slc41a1 knockdown experiments were performed to disclose SLC41A1 function in the kidney.

Results

The gene slc41a1 is ubiquitously expressed in zebrafish tissues and is regulated by water and dietary Mg²⁺ availability. Knockdown of slc41a1 resulted in renal Mg²⁺ wasting in zebrafish larvae and elicited compensatory mechanisms to cope with the renal Mg²⁺ leakage induced. These compensatory mechanisms were illustrated by an up-regulation of the gene expression of the zebrafish orthologs of human magnesiotropic genes expressed in the distal convoluted tubule (TRPM6, SLC12A3, SLC41A3 and CNNM2). Importantly, the renal Mg²⁺ wasting phenotype is rescued when mouse SLC41A1 is expressed in slc41a1-knockdown zebrafish. This proved the specificity of the knockdown approach used, as well as the functional equivalence of zebrafish Slc41a1 with the mammalian SLC41A1. Conversely, expression of mammalian SLC41A1-p.Asp262Ala, harbouring a mutation in the ion-conducting SLC41A1 pore, did not reverse the renal Mg²⁺ wasting observed in slc41a1-knockdown zebrafish. ²⁵Mg²⁺ transport assays in human embryonic kidney 293 (HEK293) cells overexpressing SLC41A1 demonstrated that SLC41A1 mediates cellular Mg²⁺ extrusion independently of sodium (Na⁺). In contrast, SLC41A1-p.Asp262Ala expressing HEK293 cells displayed similar Mg²⁺ extrusion activities than control (mock) cells. In polarized Madin-Darby Canine Kidney cells, SLC41A1 localized to the basolateral cell membrane.

Conclusion

Our results demonstrate that SLC41A1 facilitates renal Mg²⁺ reabsorption in the zebrafish model. Furthermore, our data suggest that SLC41A1 extrudes Mg²⁺ across the basolateral membrane by a mechanism that is independent of Na⁺. Based on the SLC41A1 function disclosed, patients with hereditary hypomagnesemia should be screened for SLC41A1 mutations.

Funding

• Private Foundation Support