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

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

Content Provider	Springer Nature Link
Author	Canica, Jérémie Sergi, Chloé Maillard, Marc Klusova, Petra Odermatt, Alex Koesters, Robert Loffing Cueni, Dominique Loffing, Johannes Rossier, Bernard Frateschi, Simona Hummler, Edith
Copyright Year	2016
Abstract	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 (MRPax8/LC1) using a doxycycline-inducible system. Under standard diet, MRPax8/LC1 mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MRPax8/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 MRPax8/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.
Starting Page	895
Ending Page	908
Page Count	14
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	468
Issue Number	5
e-ISSN	14322013
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-01-14
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	MR GR Thiazide-sensitive Na+/Cl− co-transporter Aldosterone Salt-losing syndrome Human Physiology
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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

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