Magnesium and Calcium Homeostasis Depend on KCTD1 Function in the Distal Nephron.

Magnesium (Mg) homeostasis depends on active transcellular Mg reuptake from urine in distal convoluted tubules (DCTs) via the Mg channel TRPM6, whose activity has been proposed to be regulated by EGF. Calcium (Ca) homeostasis depends on paracellular reabsorption in the thick ascending limbs of Henle (TALs). KCTD1 promotes terminal differentiation of TALs/DCTs, but how its deficiency affects urinary Mg and Ca reabsorption is unknown. Here, this study shows that DCT1-specific KCTD1 inactivation leads to hypomagnesemia despite normal TRPM6 levels because of reduced levels of the sodium chloride co-transporter NCC, whereas Mg homeostasis does not depend on EGF. Moreover, KCTD1 deficiency impairs paracellular urinary Ca and Mg reabsorption in TALs because of reduced NKCC2/claudin-16/-19 and increased claudin-14 expression, leading to hypocalcemia and consequently to secondary hyperparathyroidism and progressive metabolic bone disease. Thus, KCTD1 regulates urinary reabsorption of Mg and Ca by inducing expression of NCC in DCTs and NKCC2/claudin-16/-19 in TALs.