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

Magnesium (Mg(2+)) homeostasis depends on active transcellular Mg(2+) reuptake from urine in distal convoluted tubules (DCTs) via the Mg(2+) channel TRPM6, whose activity has been proposed to be regulated by EGF. Calcium (Ca(2+)) 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(2+) and Ca(2+) 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(2+) homeostasis does not depend on EGF. Moreover, KCTD1 deficiency impairs paracellular urinary Ca(2+) and Mg(2+) 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(2+) and Ca(2+) by inducing expression of NCC in DCTs and NKCC2/claudin-16/-19 in TALs.