Parathyroid hormone controls paracellular Ca2+ transport in the thick ascending limb by regulating the tight-junction protein Claudin14

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 16; pp. E3344 - E3353
• Main Authors: Sato, Tadatoshi, Courbebaisse, Marie, Ide, Noriko, Fan, Yi, Hanai, Jun-ichi, Kaludjerovic, Jovana, Densmore, Michael J., Yuan, Quan, Toka, Hakan R., Pollak, Martin R., Hou, Jianghui, Lanske, Beate
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 18.04.2017
• Series: PNAS Plus
• Subjects: Biological Sciences; Calcium; Calcium (blood); Calcium (urinary); Calcium homeostasis; Calcium ions; Calcium transport; Distal tubules; Flow cytometry; Gene deletion; Homeostasis; Hypercalciuria; Hypoparathyroidism; Kidneys; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Phenotypes; Phosphates; PNAS Plus; Proteins; Reabsorption; Signal transduction; Signaling; Translocation; Tubules
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1616733114

Renal Ca2+ reabsorption is essential for maintaining systemic Ca2+ 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;Pth1rfl/fl . Mutant mice exhibited hypercalciuria and had lower serum calcium and markedly increased serum PTH levels. Unexpectedly, proteins involved in transcellular Ca2+ reabsorption in DCTs were not decreased. However, claudin14 (Cldn14), an inhibitory factor of the paracellular Ca2+ 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;Pth1rfl/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 Ca2+ 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;Pth1rfl/fl mice, emphasizing the importance of PTH in inhibiting Cldn14. Consequently, suppressing CLDN14 could provide a potential treatment to correct urinary Ca2+ loss, particularly in patients with hypoparathyroidism.