title: Osmoregulation requires brain expression of the renal Na-K-2Cl cotransporter NKCC2.
abstract: The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABA-mediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Konopacka
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Song T
authors.identifier: http://orcid.org/0000-0003-3337-4490
authors.initials: ST
authors.lastname: Yao
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Greenwood
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Mingkwan
authors.initials: M
authors.lastname: Greenwood
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lancaster
authors.affiliation: Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1.
authors.forename: Wataru
authors.initials: W
authors.lastname: Inoue
authors.affiliation: Department of Physiological Sciences, Biology Institute, Federal Rural University of Rio de Janeiro, Seropedica Rio de Janeiro, Brazil 23897-970, Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 50603, Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil 14090-900.
authors.forename: Andre de Souza
authors.initials: AS
authors.lastname: Mecawi
authors.affiliation: Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil 14090-900.
authors.forename: Fernanda M V
authors.initials: FM
authors.lastname: Vechiato
authors.affiliation: Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil 14090-900.
authors.forename: Juliana B M
authors.initials: JB
authors.lastname: de Lima
authors.affiliation: Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil 14090-900.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Coletti
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 50603.
authors.forename: See Ziau
authors.initials: SZ
authors.lastname: Hoe
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Martin
authors.affiliation: School of Chemical and Life Sciences, Nanyang Polytechnic, Singapore 569830, and.
authors.forename: Justina
authors.initials: J
authors.lastname: Lee
authors.affiliation: School of Chemical and Life Sciences, Nanyang Polytechnic, Singapore 569830, and.
authors.forename: Marina
authors.initials: M
authors.lastname: Joseph
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom, Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 50603.
authors.forename: Charles
authors.initials: C
authors.lastname: Hindmarch
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Paton
authors.affiliation: Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil 14090-900.
authors.forename: Jose
authors.initials: J
authors.lastname: Antunes-Rodrigues
authors.affiliation: Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Bains
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom, Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 50603, d.murphy@bristol.ac.uk.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-2946-0353
authors.initials: D
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood / Q000187:drug effects; D002034:Bumetanide / Q000494:pharmacology; D003681:Dehydration / Q000503:physiopathology; D005665:Furosemide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020644:Midline Thalamic Nuclei / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009897:Optic Chiasm / Q000502:physiology; D064587:Osmoregulation / Q000502:physiology*; D010904:Pituitary Gland, Posterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064466:Solute Carrier Family 12, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology
chemical_list: D034741:RNA, Small Interfering; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064466:Solute Carrier Family 12, Member 1; D002034:Bumetanide; D001127:Arginine Vasopressin; D005665:Furosemide
keywords: GABA; Slc12a1/NKCC2; fluid balance; hypothalamo-neurohypophyseal system; loop diuretics
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