Higher dietary salt intake in humans is associated with higher BP, but the BP response to NaCl, so-called salt sensitivity, is heterogeneous among individuals. It has been postulated that modifications in cellular cation metabolism may be related to salt sensitivity in mammalian hypertension. The authors have isolated a novel rat complementary DNA, called salt-tolerant protein (STP), that can functionally complement Saccharomyces cervisiae HAL1, which improves salt tolerance by modulating the cation transport system. On high-salt (8% NaCl) diets, both Dahl salt-sensitive and salt-resistant rats displayed an elevated BP and increased STP mRNA expression. Immunohistochemistry using an anti-rat STP antibody demonstrated the presence of STP immunoreactivity in the proximal tubules. In cells that transiently expressed STP, the intracellular [Na+]/[K+] ratio was higher than that in control cells. STP contains predicted coiled-coil and Src homology 3 domains, and shows a partially high degree of nucleotide identity to human thyroid-hormone receptor interacting protein. These results suggest that STP may play an important role in salt sensitivity through cellular sodium metabolism by mediating signal transduction and a hormone-dependent transcription mechanism.