Genetic drivers of age-related changes in urinary magnesium excretion.

Abstract

Although age-dependent alterations in urinary magnesium (Mg2+) excretion have been described, the underlying mechanism remains elusive. As heritability significantly contributes to variations in urinary Mg2+excretion, we measured urinary Mg2+ excretion at different ages in a cohort of genetically variable Diversity Outbred (DO) mice. Compared to animals aged 6 months, an increase in Mg2+ excretion was observed at 12 and 18 months. Quantitative trait locus (QTL) analysis revealed an association of a locus on chromosome 10 with Mg2+ excretion at 6 months of age, with Oit3 (encoding oncoprotein-induced transcript 3; OIT3) as our primary candidate gene. To study the possible role of OIT3 in renal Mg2+ handling, we generated and characterized Oit3 knockout (Oit3-/-) mice. Although a slightly lower serum Mg2+ concentration was present in male Oit3-/- mice, this effect was not observed in female Oit3-/- mice. Additionally, urinary Mg2+ excretion and the expression of renal magnesiotropic genes was unaltered in Oit3-/- mice. For animals aged 12 and 18 months, QTL analysis revealed an association with a locus on chromosome 19, which contains the gene encoding TRPM6, a known Mg2+ channel involved in renal Mg2+ reabsorption. Comparison with RNAseq data revealed that Trpm6 mRNA expression is inversely correlated with the QTL effect, implying that TRPM6 may be involved in age-dependent changes in urinary Mg2+ excretion in mice. In conclusion, we show here that variants in Oit3 and Trpm6 are associated with urinary Mg2+ excretion at distinct periods in life, although OIT3 is unlikely to affect renal Mg2+ handling.