Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2021 Jan 12;34(2):108616. doi: 10.1016/j.celrep.2020.108616.
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.
镁（Mg）稳态依赖于远端卷曲小管（DCT）中通过 Mg 通道 TRPM6 进行的主动细胞间 Mg 重吸收，其活性被提议受 EGF 调节。钙（Ca）稳态依赖于 Henle 升支粗段（TALs）中的细胞旁重吸收。KCTD1 促进 TALs/DCTs 的终末分化，但它的缺乏如何影响尿 Mg 和 Ca 重吸收尚不清楚。本研究表明，尽管 TRPM6 水平正常，但 DCT1 特异性 KCTD1 失活会导致低镁血症，原因是氯化钠共转运蛋白 NCC 的水平降低，而 Mg 稳态不依赖于 EGF。此外，KCTD1 缺乏会降低 NKCC2/ Claudin-16/-19 和增加 Claudin-14 的表达，从而损害 TALs 中的细胞旁尿 Ca 和 Mg 重吸收，导致低钙血症，进而导致继发性甲状旁腺功能亢进和进行性代谢性骨病。因此，KCTD1 通过在 DCTs 中诱导 NCC 的表达和在 TALs 中诱导 NKCC2/Claudin-16/-19 的表达来调节尿 Mg 和 Ca 的重吸收。
