Abstract
Constitutive Nedd4‐2 knockout (KO) mice show Na+ retention and salt‐sensitive hypertension. To determine the role of renal Nedd4‐2 in adult mice, we generated inducible renal tubule‐specific Nedd4‐2 KO mice (Nedd4‐2Pax8/LC1) using a combination of the Tet‐On and Cre‐loxP systems. Under standard and high‐Na+ diets, KO displayed decreased plasma aldosterone but normal Na+/K+ balance. Under high Na+ diet, KO mice showed hypercalciuria and hypertension, both treated by thiazides. NCC expression and phosphorylation were increased in the KO. Interestingly, KO showed increased intracellular β‐ and γENaC abundance, but decreased α‐ and γENaC proteolytic cleavage and decreased αENaC mRNA and protein expression, suggesting down‐regulated ENaC. In contrast, ROMK protein expression and cell surface localization were increased in the distal convoluted tubules and connecting tubules of KO, in keeping with the absence of hyperkalemia. Thus, in adult mice, loss of renal Nedd4‐2 causes a pseudohypoaldosteronism type II‐like syndrome with NCC up‐regulation leading to salt‐sensitive hypertension and hypercalciuria, suggesting that Nedd4‐2 primarily targets NCC. The accompanying hypoaldosteronism with down‐regulation of ENaC‐mediated Na+ reabsorption together with an up‐regulation of K+ secretion via ROMK likely contributes to the compensated phenotype of the KO mice and explains the maintained Na+/K+ balance.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.