serval:BIB_2AB5D125C7E3
Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.
10.1007/s00424-015-1785-2
26762397
000374842800013
Canonica
J.
author
Sergi
C.
author
Maillard
M.
author
Klusonova
P.
author
Odermatt
A.
author
Koesters
R.
author
Loffing-Cueni
D.
author
Loffing
J.
author
Rossier
B.
author
Frateschi
S.
author
Hummler
E.
author
article
2016-05
2016-05
Pflugers Archiv : European journal of physiology
1432-2013
0031-6768
journal
468
5
895-908
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.
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
eng
60_published
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
University of Lausanne
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