title: Endothelin-1 mediates natriuresis but not polyuria during vitamin D-induced acute hypercalcaemia.
abstract: Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling.
  
  
  
  Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein β and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138 team 3, Centre de Recherche des Cordeliers, CNRS ERL 8228, Paris, France.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tokonami
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138 team 3, Centre de Recherche des Cordeliers, CNRS ERL 8228, Paris, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Cheval
authors.affiliation: University of Geneva, Department of Cell Physiology and Metabolism, Service of Nephrology University Medical Center, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Monnay
authors.affiliation: Bioinformatic Core Facility, UMS AMMICA, INSERM US23, CNRS UMS3665, Gustave Roussy, Villejuif, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Meurice
authors.affiliation: University of Zurich, Institute of Anatomy, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: University of Geneva, Department of Cell Physiology and Metabolism, Service of Nephrology University Medical Center, Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Feraille
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138 team 3, Centre de Recherche des Cordeliers, CNRS ERL 8228, Paris, France.
authors.forename: Pascal
authors.identifier: 0000-0003-4953-6917
authors.initials: P
authors.lastname: Houillier
mesh_terms: D000208:Acute Disease; D000818:Animals; D002461:Cell Line, Transformed; D019332:Endothelin-1 / Q000502:physiology*; D006934:Hypercalcemia / Q000139:chemically induced / Q000378:metabolism* / Q000652:urine; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D011141:Polyuria / Q000378:metabolism* / Q000652:urine; D014807:Vitamin D / Q000633:toxicity*
chemical_list: D019332:Endothelin-1; D014807:Vitamin D
keywords: distal nephron; endothelin; hypercalcemia; odium balance