Abstract Body: Salt-sensitive hypertension is a condition in which blood pressure (BP) increases in response to an increase in a salt intake. This condition is influenced by a complex interplay among environmental, lifestyles, and genetic factors. Salt sensitivity has been shown to be associated with specific genetic variants in the human G protein-coupled receptor kinase 4γ (hGRK4γ) gene. Recent findings from our laboratory demonstrated the expression of neuropeptide FF (NPFF) and its receptors in human and mouse renal proximal tubule cells, variants of which have also been associated with increased BP. Furthermore, the renal-selective, renal subcapsular infusion of physiological concentrations of NPFF led to a decrease in urinary sodium excretion and an increase in BP. These findings suggested the involvement of this system in the regulation of blood pressure. The present study was designed to test the hypothesis that renal NPFF is involved in salt-sensitive hypertension. To this end, a study was conducted in two models of salt sensitivity in mice. The first model involved transgenic mice expressing the hGRK4γ 486 variant (hGRK4γ 486V) and their controls expressing the hGRK4 wild-type (hGRK4γ WT) transgene. The second model involved mice expressing the hGRK4γ 65L variant (hGRK4γ 65L) and their controls, expressing the hGRK4γ wild-type (hGRK4γ WT) transgene. The mice were studied after one week on a normal salt diet (NS; 0.8% NaCl) and after one week on high salt (HS; 4% NaCl) diet. BP was measured by telemetry. On NS diet hGRK4γ 486V had BPs similar to hGRK4γ WT mice while on HS the BPs were higher in hGRK4γ 486V than in hGRK4γ WT mice (124±1.5 vs 105±2.3 mm Hg; n=6-8/ group; P<0.05). On NS diet the renal NPFF mRNA expression was higher (1.5 ± 0.09-fold; P<0.05; n=3-4/group) in hGRK4γ 486V than in hGRK4γ WT mice. A change to HS diet increased NPFF mRNA expression in hGRK4γ WT (1.8±fold; P<0.05; n=6-8/group) but not in hGRK4γ 486V mice. On NS diet hGRK4γ 65L had BPs similar to hGRK4γ WT mice but on HS diet BPs were higher in hGRK4γ 65L than in hGRK4γ WT mice (120±6 vs 104±3.1 mmHg; n=4-6/ group; P<0.05). By contrast, renal NPFF expression was similar in hGRK4γ 65L and hGRK4γ WT on both diets. There were no differences in NPFF mRNA receptors expression in any of the groups. The results of the present study indicate that NPFF may be involved in the pathogenesis of salt sensitivity in hGRK4γ 486V but not in hGRK4γ 65L mice.