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Abstract: PO1814

Deletion of the Dopamine D2 Receptor in the Renal Proximal Tubule Increases Blood Pressure on Low-Salt Diet and Decreases Blood Pressure on High-Salt Diet: A Case of Inverse Salt Sensitivity

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Asico, Laureano D., The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
  • Moore, Shaun Christopher, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
  • Jose, Pedro A., The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
  • Armando, Ines, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
Background

The dopamine D2 receptor D2 (D2R) in the kidney is important in maintaining normal blood pressure (BP) and preventing inflammation and tissue injury. Global D2R gene (Drd2) knockdown i or renal-selective D2R downregulation in the mouse increases BP and results in renal inflammation, tubular injury, and fibrosis. To study the function of D2R in the renal proximal tubule, we generated Drd2fl/fl, PSGLT2::Cre+ mice (D2RPT-/-) that lack D2R only in the renal proximal tubule and Drd2fl/fl, PSGLT2::Cre- (D2RPT+/+) mice that do not have the deletion.

Methods

Mice were genotyped for Drd2fl/fl and a smaller amplicon representing the Cre deletion mutant. We studied male mice on normal salt (NS; 0.4% NaCl), high (HS; 4% NaCl), and low (LS; <0.08% NaCl) diets.

Results

On NS diet, male D2RPT-/- had slightly higher BP, measured under anesthesia, than male D2RPT+/+ mice (106±1 vs 101±2 mmHg, n=15/group; P<0.05). On HS diet D2RPT-/- mice had lower BP than D2RPT+/+ (100±3 vs 107±2 mmHg; P<0.04; n=12) but on LS diet D2RPT-/- had higher BP than D2RPT+/+ mice (126±5 vs 103±4 mmHg; P<0.01; n=7). Both the decrease in BP on HS diet and the increase in BP on LS diet, relative to BP on NS diet, were confirmed by telemetry in conscious mice. These data indicated that D2R deletion only in the renal proximal tubule impairs the normal responses to changes in salt intake. On NS diet the renal mRNA expressions of NHE3, Na+/K+ATPase, and NCC were similar in both groups of mice. On HS diet NHE3 and NCC were lower in D2RPT-/- than D2RPT+/+ mice (NHE3: 0.7±0.02 vs 1.0±0.03 fold-change; P<0.05,n=4-5/group; NCC: 0.5±0.1 vs 1.0±0.09 fold-change; P<0.05) while Na+/K+ATPase was similar in both groups. On LS diet NHE3, Na+/K+ATPase, and NCC expression were higher (P<0.05) in D2RPT-/- than in D2RPT+/+ mice.

Conclusion

There are marked differences in the response to changes in dietary salt intake on BP and renal expression of sodium exchanger/transporter/pump in mice lacking D2R only in the renal proximal tubule that is accompanied by increased inflammation and fibrosis. There results may have significant clinical implications since in humans, the presence of D2R variants, DRD2 rs6276 and rs6277, which decrease D2R protein/function, is associated with inverse salt sensitivity.

Funding

  • Other NIH Support