Atrial natriuretic peptide (ANP) has negative modulatory effects on a variety of pathophysiologic mechanisms, i.e., inhibits hypoxia-induced pulmonary vasoconstriction and vascular remodeling and facilitates natriuresis and vasorelaxation in NaCl-supplemented subjects. We have previously demonstrated organ-selective potentiation of ANP in the pulmonary circulation of hypoxia adapted animals by local down-regulation of its clearance receptor (NPR-C). The current study tested the hypothesis that NPR-C expression is attenuated selectively in kidney of NaCl-supplemented subjects. Adult male wild-type (ANP+/+) and homozygous mutant (ANP-/-) mice were studied after 5 wks of normal or high-salt diets. Mean arterial pressure (MAP) and left (LV) and right ventricular (RV) mass were greater in ANP-/- mice than in ANP+/+ mice fed the normal salt diet; salt supplementation induced increases in plasma ANP in ANP+/+ mice and in MAP and LV, RV and renal mass in ANP-/- mice, but not in ANP+/+ mice. NPR-C mRNA levels were selectively and significantly reduced (>60%) in kidney, but not in lung, brain, LV or RV, by dietary salt supplementation in both genotypes. NPR-A mRNA levels did not differ among diet-genotype groups in any organ studied. Cyclic GMP content was significantly increased in kidney, but not in lung or brain, by dietary salt supplementation in both genotypes. These findings suggest that selective down-regulation of NPR-C in the kidney in response to dietary salt supplementation may contribute to local elevation in ANP levels and may be functionally significant in attenuating the development of salt-sensitive hypertension.