Magnesium Handling in the Kidney

Abstract

Magnesium is a divalent cation that fills essential roles as regulator and cofactor in a variety of biological pathways, and maintenance of magnesium balance is vital to human health. The kidney, in concert with the intestine, has an important role in maintaining magnesium homeostasis. Although micropuncture and microperfusion studies in the mammalian nephron have shone a light on magnesium handling in the various nephron segments, much of what we know about the protein mediators of magnesium handling in the kidney have come from more recent genetic studies. In the proximal tubule and thick ascending limb, magnesium reabsorption is believed to occur primarily through the paracellular shunt pathway, which ultimately depends on the electrochemical gradient setup by active sodium reabsorption. In the distal convoluted tubule, magnesium transport is transcellular, although magnesium reabsorption also appears to be related to active sodium reabsorption in this segment. In addition, evidence suggests that magnesium transport is highly regulated, although a specific hormonal regulator of extracellular magnesium has yet to be identified.

Keywords: Claudins; Homeostasis; Kidney reabsorption; Magnesium; Nephrons.

Figure 1.. Relationship of plasma values to magnesium reabsorption in the kidney.

The percentage of magnesium reabsorbed by the major sites of transport in the kidney is illustrated relative to serum magnesium (increasing from left to right). As serum magnesium (and thus the amount of magnesium filtered by the kidney) increases, the percentage of filtered magnesium reabsorbed by the thick ascending limb of the Loop of Henle (TAL) and distal convoluted tubule (DCT) decreases. Compare this with the proximal tubule (PT), which reabsorbs magnesium in constant proportion to the amount filtered. The solid line represents total magnesium absorption by the kidney. The normal range of serum magnesium, 1.6-2.3 mg/dL, falls within the shaded area. Figure was adapted using data from Carney and colleagues and Wong and colleagues and Wong .

Figure 2.. Magnesium transport in the Thick Ascending Limb of the Loop of Henle (TAL).

Magnesium transport in the cortical TAL primarily occurs through the paracellular shunt pathway, driven by a highly positive lumen potential. The lumen potential produced is a result of active sodium transport by NKCC2 at the apical membrane and consequent apical backflux of potassium via ROMK and basolateral chloride reabsorption via Clc-Kb. Paracellular magnesium permeability is increased by claudins-16 and -19 and decreased by claudin-14. Major pathways in the regulation of TAL magnesium transport occur through activation of basolateral receptors CaSR or PTH1R. Claudin-14 expression is decreased by activation of PTH1R and increased by activation of CaSR, thus altering magnesium permeability and reabsorption in the TAL.

Figure 3.. Magnesium transport in the Distal Convoluted Tubule (DCT).

Magnesium transport in the DCT is an active transcellular process. Polarization of the apical membrane by the voltage gated potassium channel Kv1.1 provides the driving force for magnesium to enter the cell via the magnesium channel TRPM6. The molecular mediator of magnesium extrusion at the basolateral membrane remains unknown. Regulation of DCT magnesium transport seems to occur in part by the direct action of intracellular free magnesium. EGFR activation also leads to increased active TRPM6 at the apical membrane.