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Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Proc+Natl+Acad+Sci+U+S+A 2017 ; 114 (16): E3344-E3353 Nephropedia Template TP
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Parathyroid hormone controls paracellular Ca(2+) transport in the thick ascending limb by regulating the tight-junction protein Claudin14 #MMPMID28373577
Sato T; Courbebaisse M; Ide N; Fan Y; Hanai JI; Kaludjerovic J; Densmore MJ; Yuan Q; Toka HR; Pollak MR; Hou J; Lanske B
Proc Natl Acad Sci U S A 2017[Apr]; 114 (16): E3344-E3353 PMID28373577show ga
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.
|*Gene Expression Regulation[MESH]
|Animals[MESH]
|Calcium/*metabolism[MESH]
|Claudins/*physiology[MESH]
|Extremities/*physiology[MESH]
|Mice[MESH]
|Mice, Inbred C57BL[MESH]
|Mice, Knockout[MESH]
|Parathyroid Hormone/*metabolism[MESH]
|Promoter Regions, Genetic/genetics[MESH]
|Receptor, Parathyroid Hormone, Type 1/*metabolism[MESH]