CHIF (corticosteroid hormone-induced factor) is a member of the FXYD family that shares approximately 50% homology with the gamma subunit of Na,K-ATPase. It is expressed in renal collecting duct and distal colon, and is upregulated by Na(+) deprivation and high K(+) diet. Both CHIF and gamma are coimmunoprecipitated by an anti-alpha subunit antibody, and alpha is immunoprecipitated by anti-gamma and anti-CHIF antibodies. (86)Rb(+) flux experiments in CHIF-transfected HeLa cells demonstrate that CHIF increases the affinity for cytoplasmic Na(+), but does not affect the affinity for extracellular K(Rb). A physiological role of CHIF in kidney function is further elucidated by the phenotypic analysis of CHIF knockout mice. Taken together with data by others, it appears that FXYD proteins are tissue-specific subunits or regulators of the Na,K-ATPase whose function is to adjust the pump kinetics to particular physiological needs.