Renal magnification by EGF

Abstract

A paper recently published by Groenestege and colleagues [8] used positional cloning to determine the cause of a rare inherited magnesium-wasting syndrome, autosomal recessive renal hypomagnesemia. The results showed that certain mutations in the epidermal growth factor (EGF) gene cause this disease. This suggests, perhaps surprisingly, that EGF and its receptor comprise a previously unrecognized signaling pathway in the human kidney that participates importantly in magnesium homeostasis. The EGF gene is highly expressed along the distal convoluted tubule (DCT), an important site for regulating urinary magnesium excretion. The product of the gene is a large membrane-bound molecule, expressed at both the apical and basolateral surfaces. A portion of the extracellular domain can be cleaved to form the 53-amino-acid hormone, EGF; it is believed that cleavage occurs preferentially at the basolateral surface, leading to increased apparent EGF abundance at the apical membrane. In the DCT, EGF binds to receptors at the basolateral surface, making basolateral EGF expression a necessary prerequisite for signaling. The gene defect that causes autosomal recessive renal hypomagnesemia appears to disrupt trafficking of pro-EGF to the basolateral membrane, thereby impeding its signaling capability. The results also showed that EGF stimulates magnesium transport by TRPM6 (transient receptor potential cation channel, subfamily M, member 6), a channel that is expressed at the apical membrane of DCT cells and appears to be a primary path for apical magnesium entry. Interestingly, the investigators also corroborated previous reports that cancer patients treated with an antagonist of the EGF receptor, cetuximab, develop renal magnesium wasting and hypomagnesemia, emphasizing the significance of EGF in maintaining magnesium balance in humans.

Fig. 1

Model of distal convoluted tubule (DCT) and thick ascending limb (TAL) cells, showing predominant magnesium transport pathways. DCT cell shows magnesium entering the cell via TRPM6 (TRPM7 may also play a role). This channel is positively regulated by EGF activation of its receptor, which lies only in the basolateral membrane. Note that pro-EGF is expressed at both apical and basolateral membranes, but cleavage to EGF occurs predominantly at the basolateral side. Other transport pathways that affect magnesium transport include the Na–Cl cotransporter (NCC), and the Na/K ATPase. Causes of inherited magnesium wasting disorders are indicated. Proposed mechanisms of drug-induced magnesium wasting are also shown. TAL cell shows magnesium traversing the epithelium (with calcium) paracellularly, via claudin-16 (claudin-19, not shown, may also be involved). Causes of inherited magnesium wasting disorders are shown, as are proposed mechanisms of drug-induced magnesium wasting. Many aspects have been simplified or omitted, for clarity.