The Expression of the Dopamine D2 Receptor Bearing the Single Nucleotide Polymorphism rs6277 in Mice Results in Inverse Salt Sensitivity of Blood Pressure

One-third of individuals without underlying health conditions and 60% of individuals with elevated blood pressure (BP) are salt-sensitive. A shift from low to high Na + diet is linked to higher BP. Inverse salt sensitivity is an increase in BP when Na+ intake is reduced. This affects about 10-15% of the population but the mechanisms underlying this alteration in BP are not understood. The renal dopamine D2 receptor (D2R) plays a critical role in maintaining normal BP and preventing inflammation and tissue injury. The DRD2 gene is highly polymorphic and single nucleotide polymorphisms of this gene have been linked to allelic variations that impair receptor synthesis and stability. In particular, the rs6277 SNP in exon 7 of DRD2 is associated with decreased D2R expression and found in some humans with elevated blood pressure or hypertension. We have also reported that human renal proximal tubular cells with this SNP have decreased mRNA and protein D2R expressions and increased expression of Na+ pump/transporters. To study the effects of this SNP on Na + balance and BP we generated, using CRISP-Cas9, mice expressing either the human D2R wild-type ( DRD2 WT) or the mutant expressing the rs6277 ( DRD2 Mut) in mice lacking their own Drd2. Female mice were placed for one week on three distinct salt diets: normal salt (NS; 0.4% NaCl) diet, high salt (HS; 4% NaCl), and low salt (LS; less than 0.08% NaCl) diets. On NS diet, BPs (measured by tail-cuff under pentobarbital anesthesia) were similar in DRD2 WT and DRD2 Mut mice (79±3 vs 81±5 mm Hg; n=4/group). On HS diet, BPs were also similar in both groups (85±3 vs 86±5 mm Hg; n=4/group). However, on LS diet DRD2 Mut mice had significantly higher BPs than DRD2 WT (89±5 vs 71±1 mm Hg, p<0.05; n=4/group) mice. In DRD2 WT mice, BP increased on HS diet and decreased on LS, while in DRD2 Mut mice, BP increased on LS but their BPs were not different between NS and HS diet. On LS diet, UNaV was lower in DRD2 Mut than DRD2 WT mice (0.003±0.001 vs 0.008±0.001 mEq/day; p<0.05; n=4/group) but on HS diet, UnaV was higher in DRD2 Mut than DRD2 WT (0.91±0.3 vs 0.44±0.07; p<0.05; n=3/group) mice. Preliminary data in male mice show the same alterations. These findings suggest that alterations in DRD2 expression/function may be the underlying cause of inverse salt sensitivity because the presence of DRD2 rs6277 is associated with inverse salt sensitivity in humans. NIH-NIDDK R01Actf DK134574Projectf 01 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.