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

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...

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Published in:Cell reports (Cambridge) 2021-01, Vol.34 (2), p.108616-108616, Article 108616
Main Author: Marneros, Alexander G.
Format: Article
Language:English
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Summary: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. [Display omitted] •KCTD1 in early distal convoluted tubules regulates active urinary Mg2+ reabsorption•EGF is not a major regulator of Mg2+ homeostasis•Lack of KCTD1 in thick ascending limbs impairs paracellular Ca2+ and Mg2+ reabsorption•These thick ascending limb defects cause hypocalcemia and hyperparathyroidism 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.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.108616