This study was aimed at dissecting mechanisms of coordination between ENaC and Na,K-ATPase as well as between transcellular Na+ transport and paracellular permeability in renal collecting duct principal cells. Aldosterone-clamped rats fed of varying Na+ intake and mCCDcl1 cells that overexpress ?-ENaC in a doxycycline-inducible manner were used. Crosstalk between ENaC and Na,K-ATPase was observed in vivo and in vitro. Increased apical Na+ entry was invariably associated with increased basolateral Na+ extrusion via Na,K-ATPase. This was accounted for by decreased endocytosis and degradation of cell-surface Na,K-ATPase, which was mediated by inhibition of p38 kinase activity. Crosstalk between transcellular Na+ transport and paracellular permeability was also observed in cultured mCCDcl1 cells. Increased transcellular Na+ transport was associated with decreased paracellular permeability as inferred by increased transepithelial resistance. This effect was mediated by decreased ß-catenin signaling through the release of its transcriptional suppression of claudin-8 in response to increased transcellular Na+ transport.