Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine

Abstract

The body maintains Mg(2+) homeostasis by renal and intestinal (re)absorption. However, the molecular mechanisms that mediate transepithelial Mg(2+) transport are largely unknown. Transient receptor potential melastatin 6 (TRPM6) was recently identified and shown to function in active epithelial Mg(2+) transport in intestine and kidney. To define the relationship between Mg(2+) status and TRPM6 expression, we used two models of hypomagnesemia: 1) C57BL/6J mice fed a mildly or severely Mg(2+)-deficient diet, and 2) mice selected for either low (MgL) or high (MgH) erythrocyte and plasma Mg(2+) status. In addition, the mice were subjected to a severely Mg(2+)-deficient diet. Our results show that C57BL/6J mice fed a severely Mg(2+)-deficient diet developed hypomagnesemia and hypomagnesuria and showed increased TRPM6 expression in kidney and intestine. When fed a Mg(2+)-adequate diet, MgL mice presented hypomagnesemia and hypermagnesuria, and lower kidney and intestinal TRPM6 expression, compared with MgH mice. A severely Mg(2+)-deficient diet led to hypomagnesemia and hypomagnesuria in both strains. Furthermore, this diet induced kidney TRPM6 expression in MgL mice, but not in MgH mice. In conclusion, as shown in C57BL/6J mice, dietary Mg(2+)-restriction results in increased Mg(2+) (re)absorption, which is correlated with increased TRPM6 expression. In MgL and MgH mice, the inherited Mg(2+) status is linked to different TRPM6 expression. The MgL and MgH mice respond differently to a low-Mg(2+) diet with regard to TRPM6 expression in the kidney, consistent with genetic factors contributing to the regulation of cellular Mg(2+) levels. Further studies of these mice strains could improve our understanding of the genetics of Mg(2+) homeostasis.

Dysregulation of Vascular TRPM7 and Annexin-1 Is Associated With Endothelial Dysfunction in Inherited Hypomagnesemia

“…The molecular mechanisms underlying this magnesium wasting in MgL are yet to be fully elucidated; however, dysregulation of TRPM6 in both kidneys and cecum may be important. 33 It is also possible that magnesium wasting and blood pressure elevation may be attributed, at least in part, to renal dysfunction in MgL, because these mice exhibited microalbuminuria (as evidenced by higher urinary albumin:creatinine ratios in MgL compared with MgH mice). When we examined the expression of the Mg transporter TRPM7 in vascular tissue, we observed that aortas from MgL mice have a striking increase in TRPM7 mRNA levels compared with MgH mice.…”

Transient Receptor Potential Melastatin 6 Knockout Mice Are Lethal whereas Heterozygous Deletion Results in Mild Hypomagnesemia

“…Colocalization with the sodium-chloride cotransporter confirmed TRPM6 presence within the luminal membrane of DCT cells [13] . Dietary Mg 2+ restriction was shown to increase TRPM6 mRNA and protein expression in the mouse kidney [19,20] , while Mg 2+ supplementation induces TRPM6 expression in the colon [19,20] . TRPM6 expression and Mg 2+ (re)absorption are also regulated by a variety of hormones and compounds.…”

Identification of TRPM6 and TRPM7 expression changes in response to a diet supplemented with inulin in porcine kidney

“…Previous experiments conducted on mice indicated that dietary Mg deficiency and hypomagnesemia result in a significant upregulation of TRPM6 channels in the kidneys, whereas a Mg-enriched diet decreases TRPM6 expression (Groenestege et al, 2006;Rondón et al, 2008a;van Angelen et al, 2013). However, upregulation of TRPM6 in pigs fed a diet supplemented with inulin does not necessarily indicate that inulin did not improve the bioavailability of magnesium.…”