The thick ascending limb Na+/K+/2Cl− co-transporter (NKCC2) was not significantly affected by dietary NaCl or genotype. Both genotypes responded with an increased expression of total NCC in response to low NaCl intake. However, under high dietary NaCl, total NCC expression was significantly higher in NHE3loxloxCre mice compared to Con mice. Phosphorylation of pT58 NCC was increased in response to low NaCl compared to high NaCl diet in both genotypes; however, NHE3loxloxCre mice show stronger phosphorylation under both low and high NaCl diet. Full-length α-subunit of the epithelial Na+ channel (αENaC) was significantly higher in NHE3loxloxCre mice compared to Con mice under either dietary condition. Cleaved αENaC expression was not different between genotypes on a high NaCl diet; however, it was significantly higher in NHE3loxloxCre compared to Con mice on low NaCl diet. *P < 0.05 versus high NaCl same genotype, #P < 0.05 versus Con same diet.