The Epithelial Na+ Channel (ENaC) composed of three subunits (alpha, beta and gamma) is expressed at the apical membrane of lung and renal epithelia. In the kidney, ENaC is expressed in the Aldosterone-Sensitive Distal Nephron (ASDN) where it controls sodium balance, blood volume and blood pressure. Mice with ubiquitous and constitutive gene inactivation of alpha ENaC die within 48 hours from a lung alveolar fluid clearance failure and from a severe renal salt-loosing syndrome (pseudohypoaldosteronism type 1 (PHA type 1) and thus, the consequences of total deletion of alpha ENaC in the kidney cannot be observed at adulthood. Mice in which alpha ENaC is deleted specifically in the CD are viable and do not show disturbances in sodium and potassium balance even when subjected to challenging diets (Rubera et al., JCI, 2003). This suggested that the CNT is important in controlling ENaC-mediated sodium reabsorption in the kidney. To investigate this further, we generated mice in which the alpha ENaC gene was deleted in the CD and partly in the CNT. These mice are viable until adulthood and exhibit normal BP, although they show increased urinary sodium excretion, urine output, and plasma aldosterone, leading to hyponatremia and hyperkalemia under standard diet. After sodium restriction, the mice develop a severe salt-losing phenotype and show a continuous life-threatening reduction of body weight (Christensen et al., JASN, 2010). Recently, we induced acutely a complete knockout of alpha and gamma ENaC along the whole nephron of adult animals. Thus, genetically engineered mice lacking the alpha or gamma ENaC subunit in the whole nephron have been developed using a tetracycline-inducible Cre system (Pax8-rTta/LC1; Traykova-Brauch M. et al., Nat. Med., 2008) active along the entire nephron, except the glomeruli with the floxed Scnn1a mouse (Hummler E. et al., Genesis, 2002). Upon normal salt diet and following five days of doxycycline treatment, 4 week-old alpha and gamma ENaC nephron-specific knockout mice kept loosing body weight, whereas control mice continued to gain weight normally. The XXX a KO mice develop a severe and lethal PHA-1 phenotype and are hyponatremic and severely hyperkalemic with daily cumulative loss of urinary sodium and gain of urinary potassium. Whereas, surprisingly, XXX ENaC KO mice are normonatremic but severely hyperkalemic with no significant daily cumulative loss of urinary sodium but a dramatic cumulative gain of urinary potassium. This unexpected dissociation between Na+ and K+ transport suggest that K+ secretion is no longer tightly coupled to sodium reabsorption along the entire (or some part) of the ASDN.