PMID- 26762397
OWN - NLM
STAT- MEDLINE
DCOM- 20170410
LR  - 20181113
IS  - 1432-2013 (Electronic)
IS  - 0031-6768 (Linking)
VI  - 468
IP  - 5
DP  - 2016 May
TI  - Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.
PG  - 895-908
LID - 10.1007/s00424-015-1785-2 [doi]
AB  - 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 alphaENaC 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.
FAU - Canonica, Jeremie
AU  - Canonica J
AD  - Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 
      27, CH-1011, Lausanne, Switzerland.
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
FAU - Sergi, Chloe
AU  - Sergi C
AD  - Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 
      27, CH-1011, Lausanne, Switzerland.
FAU - Maillard, Marc
AU  - Maillard M
AD  - Service of Nephrology Department, University Hospital of Lausanne (CHUV), 
      Lausanne, Switzerland.
FAU - Klusonova, Petra
AU  - Klusonova P
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
AD  - Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
FAU - Odermatt, Alex
AU  - Odermatt A
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
AD  - Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
FAU - Koesters, Robert
AU  - Koesters R
AD  - Hopital Tenon, Universite Pierre et Marie Curie, Paris, France.
FAU - Loffing-Cueni, Dominique
AU  - Loffing-Cueni D
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Loffing, Johannes
AU  - Loffing J
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Rossier, Bernard
AU  - Rossier B
AD  - Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 
      27, CH-1011, Lausanne, Switzerland.
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
FAU - Frateschi, Simona
AU  - Frateschi S
AD  - Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 
      27, CH-1011, Lausanne, Switzerland.
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland.
FAU - Hummler, Edith
AU  - Hummler E
AD  - Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 
      27, CH-1011, Lausanne, Switzerland. Edith.Hummler@unil.ch.
AD  - National Center of Competence in Research "Kidney.CH", Lausanne, Switzerland. 
      Edith.Hummler@unil.ch.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160114
PL  - Germany
TA  - Pflugers Arch
JT  - Pflugers Archiv : European journal of physiology
JID - 0154720
RN  - 0 (Epithelial Sodium Channels)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Receptors, Mineralocorticoid)
RN  - 0 (Sodium Chloride Symporters)
RN  - 4964P6T9RB (Aldosterone)
RN  - 9NEZ333N27 (Sodium)
RN  - RWP5GA015D (Potassium)
SB  - IM
MH  - Aldosterone/blood
MH  - Animals
MH  - Epithelial Cells/metabolism
MH  - Epithelial Sodium Channels/genetics/metabolism
MH  - Gene Deletion
MH  - Mice
MH  - Nephrons/*metabolism
MH  - *Phenotype
MH  - Potassium/blood/urine
MH  - Pseudohypoaldosteronism/genetics/*metabolism/pathology
MH  - Receptors, Glucocorticoid/genetics/metabolism
MH  - Receptors, Mineralocorticoid/*deficiency/genetics/metabolism
MH  - Sodium/blood/urine
MH  - Sodium Chloride Symporters/genetics/metabolism
MH  - Weight Loss
OTO - NOTNLM
OT  - Aldosterone
OT  - GR
OT  - MR
OT  - Salt-losing syndrome
OT  - Thiazide-sensitive Na+/Cl- co-transporter
EDAT- 2016/01/15 06:00
MHDA- 2017/04/11 06:00
CRDT- 2016/01/15 06:00
PHST- 2015/11/20 00:00 [received]
PHST- 2015/12/27 00:00 [accepted]
PHST- 2015/12/21 00:00 [revised]
PHST- 2016/01/15 06:00 [entrez]
PHST- 2016/01/15 06:00 [pubmed]
PHST- 2017/04/11 06:00 [medline]
AID - 10.1007/s00424-015-1785-2 [pii]
AID - 10.1007/s00424-015-1785-2 [doi]
PST - ppublish
SO  - Pflugers Arch. 2016 May;468(5):895-908. doi: 10.1007/s00424-015-1785-2. Epub 2016 
      Jan 14.