Magnesium and Calcium Homeostasis Depend on KCTD1 Function in the Distal Nephron.
Magnesium and Calcium Homeostasis Depend on KCTD1 Function in the Distal Nephron.
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DOI：
10.1016/j.celrep.2020.108616
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发表时间：
2021-01-12
期刊：
影响因子：
8.8
通讯作者：
Marneros AG
中科院分区：
文献类型：
--
作者：
Marneros AG
镁离子的动态平衡依赖于远端曲管(DCT)通过镁离子通道TRPM6从尿液中主动地重新摄取镁离子，其活性被认为是由EGF调节的。钙(Ca~(2+))的动态平衡依赖于粗大的Henle升支(TALS)的细胞旁重吸收。KCTD1促进TALS/DCTs的终末分化，但其缺陷如何影响尿中的镁离子和钙离子重吸收尚不清楚。在这里，这项研究表明，尽管TRPM6水平正常，但DCT1特异的KCTD1失活会导致低镁血症，这是因为氯化钠共转运体NCC水平降低，而镁离子的稳态不依赖于EGF。此外，由于NKCC2/claudin-16/-19的减少和claudin-14表达的增加，KCTD1缺乏损害了TALS细胞旁尿钙和镁的重吸收，导致低钙血症，从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通过诱导DCT中NCC和TALS中NKCC2/claudin-16/-19的表达来调节尿中镁和钙的重吸收。Marneros指出，KCTD1缺乏所致的远端肾单位缺陷损害了远端曲小管(DCT)的跨细胞镁离子重吸收和粗大的Henle升支(TALS)的细胞旁钙镁重吸收。缺乏KCTD1的小鼠出现低镁血症和低钙血症，导致继发性甲状旁腺功能亢进症，从而导致进行性代谢性骨病。
Magnesium (Mg2+) homeostasis depends on active transcellular Mg2+ reuptake from urine in distal convoluted tubules (DCTs) via the Mg2+ channel TRPM6, whose activity has been proposed to be regulated by EGF. Calcium (Ca2+) 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 Mg2+ and Ca2+ 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 Mg2+ homeostasis does not depend on EGF. Moreover, KCTD1 deficiency impairs paracellular urinary Ca2+ and Mg2+ 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 Mg2+ and Ca2+ by inducing expression of NCC in DCTs and NKCC2/claudin-16/-19 in TALs. Marneros shows that distal nephron defects from KCTD1 deficiency impair urinary transcellular Mg2+ reabsorption in distal convoluted tubules (DCTs) and paracellular Ca2+ and Mg2+ reabsorption in thick ascending limbs of Henle (TALs). Mice lacking KCTD1 develop hypomagnesemia and hypocalcemia, resulting in secondary hyperparathyroidism and consequently in progressive metabolic bone disease.
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影响因子：
9.8
作者：
Marneros, Alexander G.;Beck, Anita E.;Bamshad, Michael J.
通讯作者：
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影响因子：
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影响因子：
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作者：
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