Authors: Jérémie Canonica Chloé Sergi Marc Maillard Petra Klusonova Alex Odermatt Robert Koesters Dominique LoffingCueni Johannes Loffing Bernard Rossier Simona Frateschi Edith Hummler
Publish Date: 2016/01/14
Volume: 468, Issue: 5, Pages: 895-908
Abstract
Aldosterone is the main mineralocorticoid hormone controlling sodium balance fluid homeostasis and blood pressure by regulating sodium reabsorption in the aldosteronesensitive distal nephron ASDN Germline lossoffunction mutations of the mineralocorticoid receptor MR in humans and in mice lead to the “renal” form of type 1 pseudohypoaldosteronism PHA1 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 nephronspecific MR knockout mice MRPax8/LC1 using a doxycyclineinducible 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 PHA1 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 sodiumdeficient diet Na+/Cl− cotransporter 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
Keywords: