NaCl cotransporter activity and Mg²⁺ handling by the distal convoluted tubule

The genetic disease Gitelman syndrome, knockout mice, and pharmacological blockade with thiazide diuretics have revealed that reduced activity of the NaCl cotransporter (NCC) promotes renal Mg²⁺ wasting. NCC is expressed along the distal convoluted tubule (DCT), and its activity determines Mg²⁺ entry into DCT cells through transient receptor potential channel subfamily M member 6 (TRPM6). Several other genetic forms of hypomagnesemia lower the drive for Mg²⁺ entry by inhibiting activity of basolateral Na⁺-K⁺-ATPase, and reduced NCC activity may do the same. Lower intracellular Mg²⁺ may promote further Mg²⁺ loss by directly decreasing activity of Na⁺-K⁺-ATPase. Lower intracellular Mg²⁺ may also lower Na⁺-K⁺-ATPase indirectly by downregulating NCC. Lower NCC activity also induces atrophy of DCT cells, decreasing the available number of TRPM6 channels. Conversely, a mouse model with increased NCC activity was recently shown to display normal Mg²⁺ handling. Moreover, recent studies have identified calcineurin and uromodulin (UMOD) as regulators of both NCC and Mg²⁺ handling by the DCT. Calcineurin inhibitors paradoxically cause hypomagnesemia in a state of NCC activation, but this may be related to direct effects on TRPM6 gene expression. In Umod^−/− mice, the cause of hypomagnesemia may be partly due to both decreased NCC expression and lower TRPM6 expression on the cell surface. This mini-review discusses these new findings and the possible role of altered Na⁺ flux through NCC and ultimately Na⁺-K⁺-ATPase in Mg²⁺ reabsorption by the DCT.