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Query: UMLS:C0020438 (
hypercalciuria
)
2,502
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Renal Ca
2+
reabsorption is essential for maintaining systemic Ca
2+
homeostasis and is tightly regulated through the parathyroid hormone (PTH)/PTHrP receptor (
PTH1R
) signaling pathway. We investigated the role of
PTH1R
in the kidney by generating a mouse model with targeted deletion of
PTH1R
in the thick ascending limb of Henle (TAL) and in distal convoluted tubules (DCTs):
Ksp-cre;Pth1r
fl/fl
Mutant mice exhibited
hypercalciuria
and had lower serum calcium and markedly increased serum PTH levels. Unexpectedly, proteins involved in transcellular Ca
2+
reabsorption in DCTs were not decreased. However, claudin14 (Cldn14), an inhibitory factor of the paracellular Ca
2+
transport in the TAL, was significantly increased. Analyses by flow cytometry as well as the use of
Cldn14-lacZ
knock-in reporter mice confirmed increased Cldn14 expression and promoter activity in the TAL of
Ksp-cre;Pth1r
fl/fl
mice. Moreover, PTH treatment of HEK293 cells stably transfected with CLDN14-GFP, together with
PTH1R
, induced cytosolic translocation of CLDN14 from the tight junction. Furthermore, mice with high serum PTH levels, regardless of high or low serum calcium, demonstrated that PTH/
PTH1R
signaling exerts a suppressive effect on Cldn14. We therefore conclude that
PTH1R
signaling directly and indirectly regulates the paracellular Ca
2+
transport pathway by modulating Cldn14 expression in the TAL. Finally, systemic deletion of Cldn14 completely rescued the hypercalciuric and lower serum calcium phenotype in
Ksp-cre;Pth1r
fl/fl
mice, emphasizing the importance of PTH in inhibiting Cldn14. Consequently, suppressing CLDN14 could provide a potential treatment to correct urinary Ca
2+
loss, particularly in patients with hypoparathyroidism.
...
PMID:Parathyroid hormone controls paracellular Ca
2+
transport in the thick ascending limb by regulating the tight-junction protein Claudin14. 2837 77
Familial hypomagnesemia with
hypercalciuria
and nephrocalcinosis (FHHNC) was previously considered to be a paracellular channelopathy caused by mutations in the claudin-16 and claudin-19 genes. Here, we provide evidence that a missense FHHNC mutation c.908C>G (p.T303R) in the claudin-16 gene interferes with the phosphorylation in the claudin-16 protein. The claudin-16 protein carrying phosphorylation at residue T303 is localized in the distal convoluted tubule (DCT) but not in the thick ascending limb (TAL) of the mouse kidney. The phosphomimetic claudin-16 protein carrying the T303E mutation but not the wildtype claudin-16 or the T303R mutant protein increases the Trpv5 channel conductance and membrane abundance in human kidney cells. Phosphorylated claudin-16 and Trpv5 are colocalized in the luminal membrane of the mouse DCT tubule; phosphomimetic claudin-16 and Trpv5 interact in the yeast and mammalian cell membranes. Knockdown of claudin-16 gene expression in transgenic mouse kidney delocalizes Trpv5 from the luminal membrane in the DCT. Unlike wildtype claudin-16, phosphomimetic claudin-16 is delocalized from the tight junction but relocated to the apical membrane in renal epithelial cells because of diminished binding affinity to ZO-1. High-Ca
2+
diet reduces the phosphorylation of claudin-16 protein at T303 in the DCT of mouse kidney via the PTH signaling cascade. Knockout of the PTH receptor,
PTH1R
, from the mouse kidney abrogates the claudin-16 phosphorylation at T303. Together, these results suggest a pathogenic mechanism for FHHNC involving transcellular Ca
2+
pathway in the DCT and identify a molecular component in renal Ca
2+
homeostasis under direct regulation of PTH.
...
PMID:Phosphorylated claudin-16 interacts with Trpv5 and regulates transcellular calcium transport in the kidney. 3148 24
