Salt-sensitive hypertension is promoted by primary alterations in renal tubular saltreabsorption. We have investigated which of the luminal NaCl transporters are involved in the maintenance of hypertension. To this end Milan hypertensive (MHS) rats, a model of salt sensitive hypertension, were studied at 3 months after birth. Na⁺-H⁺ exchanger isoform 3 (NHE3), Na⁺-K⁺-2Cl^- (NKCC2), Na⁺-Cl^- (NCC) mRNA abundance was quantified by competitive PCR. In MHS as compared to normotensive strain (MNS), mRNA abundance, on isolated tubules, was unchanged both for NHE3 and NKCC2, but higher for NCC in distal convoluted tubules (DCT). These results were confirmed by Western blot experiments, which revealed: 1. unchanged NHE3 in the cortex and NKCC2 in the outer medulla; 2. a significant increase of NCC in renal cortex; 3. a- and b-sodium channels (ENaC) unaffected in renal cortex and slightly reduced in the outer medulla, while g-ENaC remained unchanged. Pendrin protein expression was unaffected. The importance of NCC was reinforced by immunocytochemical studies showing increased NCC on the apical membrane of DCT cells of MHS animals, and by clearance experiments demonstrating a larger sensitivity to bendroflumethiazide in the same animals. These data indicate that in this model of salt sensitive hypertension there is a strong up-regulation both of the entry (NCC) and exit (ClC-K) step for NaCl transport along the DCT, which could explain the persistence of hypertension.