Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.

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Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_2AB5D125C7E3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.
Périodique
Pflugers Archiv : European journal of physiology
Auteur(s)
Canonica J., Sergi C., Maillard M., Klusonova P., Odermatt A., Koesters R., Loffing-Cueni D., Loffing J., Rossier B., Frateschi S., Hummler E.
ISSN
1432-2013 (Electronic)
ISSN-L
0031-6768
Statut éditorial
Publié
Date de publication
05/2016
Peer-reviewed
Oui
Volume
468
Numéro
5
Pages
895-908
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the "renal" form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR(Pax8/LC1)) using a doxycycline-inducible system. Under standard diet, MR(Pax8/LC1) mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR(Pax8/LC1) mice survive but develop a severe PHA-1 phenotype with higher urinary Na(+) levels, decreased plasma Na(+), hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na(+)/Cl(-) co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR(Pax8/LC1) knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na(+) and low in K(+) does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA-1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state.

Mots-clé
Aldosterone/blood, Animals, Epithelial Cells/metabolism, Epithelial Sodium Channels/genetics, Epithelial Sodium Channels/metabolism, Gene Deletion, Mice, Nephrons/metabolism, Phenotype, Potassium/blood, Potassium/urine, Pseudohypoaldosteronism/genetics, Pseudohypoaldosteronism/metabolism, Pseudohypoaldosteronism/pathology, Receptors, Glucocorticoid/genetics, Receptors, Glucocorticoid/metabolism, Receptors, Mineralocorticoid/deficiency, Receptors, Mineralocorticoid/genetics, Receptors, Mineralocorticoid/metabolism, Sodium/blood, Sodium/urine, Sodium Chloride Symporters/genetics, Sodium Chloride Symporters/metabolism, Weight Loss
Pubmed
Web of science
Création de la notice
28/05/2016 9:13
Dernière modification de la notice
20/08/2019 13:10
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