When EGF is offside, magnesium is wasted

Abstract

Our understanding of magnesium (Mg(2+)) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg(2+) homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg(2+) wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg(2+) reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg(2+) wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.

Figure 1. Renal Mg²⁺ handling.

Non–protein bound Mg²⁺ is filtered freely at the glomerulus, and the approximate percentages of filtered Mg²⁺ absorbed at different locations are shown. Under most physiologic conditions, about 10% of filtered Mg²⁺ is excreted. The final regulatory segment, the DCT, controls approximately 5% of filtered Mg²⁺. Mg²⁺ is transported by both the paracellular and transcellular pathways. Four monogenic diseases that lead to renal Mg²⁺ wasting as a result of mutations in the genes coding for the proteins shown in red have been described to date. Mutations in paracellin-1 and claudin-19 are involved in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Mutations in TRPM6 are involved in HSH. Mutations in NaCl cotransporter are involved in Gitelman syndrome, and mutations in the γ subunit of Na,K-ATPase are involved in autosomal dominant renal hypomagnesemia with hypocalciuria (ADRHH). The question mark indicates unknown pathways; the numbers 1.5, 0.6, and 0.8 indicate Mg²⁺ concentrations in moles in the lumen of the respective segment. NKCC2, Na,K-2Cl^– cotransporter.

Figure 2. Model of the autocrine/paracrine action of EGF in the DCT cell and potential mechanisms by which EGF can regulate TRPM6 activity.

Mg²⁺ influx across the luminal membrane is mediated by TRPM6 and may require the ubiquitous TRPM7. In this issue of the JCI, Groenestege et al. (11) report that EGF is a magnesiotropic hormone that regulates renal Mg²⁺ reabsorption by stimulating the EGFR, which then increases the activity of TRPM6. Aberrant targeting of pro-EGF to the basolateral membrane by the P1070L mutation results in reduced EGF production at the basolateral membrane, reduced activation of EGFR, reduced TRPM6 activity, and, consequently, Mg²⁺ wasting. Future studies should reveal which of the pathways activated by EGF mediates activation of TRPM6 and the mechanism by which TRPM6 activity is increased. As indicated by the long arrows, activation of EGFR by EGF and its tyrosine phosphorylation may directly activate TRPM6 and/or TRPM7 channel activity or may regulate insertion or retrieval or TRPM6 present in intracellular vesicular compartments. Because of the proximity of the DCT and proximal tubule, EGF generated by the DCT may activate EGFRs at the proximal tubule and therefore affect Mg²⁺ handling by this nephron segment, which reabsorbs 25% of filtered Mg²⁺. DAG, diacylglycerol; IP₃, inositol-1,4,5 trisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PLCγ, phospholipase Cγ; P, phosphate.