title: Ovarian hormones and prolactin increase renal NaCl cotransporter phosphorylation.
abstract: Unique situations in female physiology require volume retention. Accordingly, a dimorphic regulation of the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) has been reported, with a higher activity in females than in males. However, little is known about the hormones and mechanisms involved. Here, we present evidence that estrogens, progesterone, and prolactin stimulate NCC expression and phosphorylation. The sex difference in NCC abundance, however, is species dependent. In rats, NCC phosphorylation is higher in females than in males, while in mice both NCC expression and phosphorylation is higher in females, and this is associated with increased expression and phosphorylation of full-length STE-20 proline-alanine-rich kinase (SPAK). Higher expression/phosphorylation of NCC was corroborated in humans by urinary exosome analysis. Ovariectomy in rats resulted in decreased expression and phosphorylation of the cotransporter and promoted the shift of SPAK isoforms toward the short inhibitory variant SPAK2. Conversely, estradiol or progesterone administration to ovariectomized rats restored NCC phosphorylation levels and shifted SPAK expression and phosphorylation towards the full-length isoform. Estradiol administration to male rats induced a significant increase in NCC phosphorylation. NCC is also modulated by prolactin. Administration of this peptide hormone to male rats induced increased phosphorylation of NCC, an effect that was observed even using the ex vivo kidney perfusion strategy. Our results indicate that estradiol, progesterone, and prolactin, the hormones that are involved in sexual cycle, pregnancy and lactation, upregulate the activity of NCC.
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Lorena
authors.initials: L
authors.lastname: Rojas-Vega
authors.affiliation: Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Luis A
authors.initials: LA
authors.lastname: Reyes-Castro
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Victoria
authors.initials: V
authors.lastname: Ramírez
authors.affiliation: Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico;
authors.forename: Rocío
authors.initials: R
authors.lastname: Bautista-Pérez
authors.affiliation: INSERM UMR970, Paris Cardiovascular Research Center, Paris, France; University Paris-Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France;
authors.forename: Chloe
authors.initials: C
authors.lastname: Rafael
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: María
authors.initials: M
authors.lastname: Castañeda-Bueno
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Patricia
authors.initials: P
authors.lastname: Meade
authors.affiliation: Escuela de Medicina, Universidad Panamericana, Mexico City, Mexico;
authors.forename: Paola
authors.initials: P
authors.lastname: de Los Heros
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Isidora
authors.initials: I
authors.lastname: Arroyo-Garza
authors.affiliation: INSERM U693, Le Kremlin-Bicêtre Université Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Le Kremlin-Bicêtre, France; and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bernard
authors.affiliation: INSERM U693, Le Kremlin-Bicêtre Université Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Le Kremlin-Bicêtre, France; and Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin Bicêtre, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Norma A
authors.initials: NA
authors.lastname: Bobadilla
authors.affiliation: INSERM UMR970, Paris Cardiovascular Research Center, Paris, France; University Paris-Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France;
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
authors.affiliation: Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
authors.forename: Elena
authors.initials: E
authors.lastname: Zambrano
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; gamba@biomedicas.unam.mx.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
mesh_terms: D000818:Animals; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D007527:Isoenzymes; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism*; D010766:Phosphorylation; D011374:Progesterone / Q000008:administration & dosage / Q000378:metabolism*; D011388:Prolactin / Q000008:administration & dosage / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017208:Rats, Wistar; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D064486:Solute Carrier Family 12, Member 3 / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007527:Isoenzymes; D011981:Receptors, Prolactin; C578874:SLC12A3 protein, human; C578875:Slc12a3 protein, mouse; C578876:Slc12a3 protein, rat; D064486:Solute Carrier Family 12, Member 3; D011374:Progesterone; D004958:Estradiol; D011388:Prolactin; C116037:PAS domain kinases; D017346:Protein Serine-Threonine Kinases
keywords: WNK; distal convoluted tubule; hypertension; salt transport; thiazide