title: Parathyroid hormone controls paracellular Ca2+transport in the thick ascending limb by regulating the tight-junction protein Claudin14.
abstract: 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/flMutant 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 ofCldn14-lacZknock-in reporter mice confirmed increased Cldn14 expression and promoter activity in the TAL ofKsp-cre;Pth1rfl/flmice. 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 inKsp-cre;Pth1rfl/flmice, 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.
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.|Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.|Faculté de Médecine, Paris Descartes University, INSERM U1151-CNRS UMR8253, 75006 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Courbebaisse
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ide
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.|Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Hanai
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.
authors.forename: Jovana
authors.initials: J
authors.lastname: Kaludjerovic
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Densmore
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: Hakan R
authors.initials: HR
authors.lastname: Toka
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
authors.affiliation: Department of Internal Medicine, Washington University Renal Division, Washington University, St. Louis, MO 63130.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Hou
authors.affiliation: Division of Bone and Mineral Research, Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; beate_lanske@hsdm.harvard.edu.|Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D057167:Claudins / Q000502:physiology*; D005121:Extremities / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000502:physiology*
chemical_list: D057167:Claudins; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D002118:Calcium; C422064:claudin 14
keywords: CLDN14; PTH1R; hypercalciuria; mouse kidney; paracellular