A low salt diet increases blood pressure in mice with selective deletion of the dopamine D2 receptor in the renal proximal tubule

Abstract

The renal dopamine D2 receptor D2 (D2R) contributes in maintaining normal blood pressure (BP) and prevents inflammation and tissue injury. In mice, global deletion of the D2R gene (Drd2) or renal‐selective downregulation of the receptor increases BP and results in renal inflammation, tubular injury, and fibrosis. We studied the function of D2R in the renal proximal tubule, by generating Drd2fl/fl,PSGLT2::Cre+mice (D2R PT‐/‐) that lack D2R only in the renal proximal tubule and Drd2fl/fl,PSGLT2::Cre‐(D2R PT+/+) mice that do not have the deletion. Mice were genotyped for Drd2fl/fland a smaller amplicon representing the Cre deletion mutant. We studied male mice on normal salt (NS; 0.8% NaCl), high (HS; 4% NaCl), and low (LS;<0.05% NaCl) diets. On NS diet, male D2RPT‐/‐ had slightly higher BP, measured under anesthesia, than male D2RPT+/+mice (108±2 vs 102±2 mmHg, n=17‐21/group; P<0.05). On HS diet D2RPT‐/‐ had lower BP than D2RPT+/+ (100±3 vs 108±1 mmHg; P<0.04; n=12) but on LS diet D2RPT‐/‐ had higher BP than D2RPT+/+ (130±5 vs 103±4 mmHg; P<0.01; n=8). BP measured by telemetry in conscious mice confirmed the decrease in BP on HS diet and the increase in BP on LS diet, relative to BP on NS diet. The data indicated that the normal response to changes in salt intake is impaired by the deletion of the D2R only in the renal proximal tubule. On NS diet, the renal protein expressions of NHE3, Na+/K+ATPase, and NCC were similar in both groups of mice but NKCC2 was higher in D2RPT‐/‐ (190 ±5% vs 100±20; P<0.05) than in D2RPT+/+. On HS diet, Na+/K+ATPase was lower (110±5% vs 220±3%; P<0.05) but NKCC2 was higher (290±9% vs 200±5%,P<0.05) in D2RPT‐/‐ while NHE3 and NCC were similar in both groups. On LS diet, NHE3, Na+/K+ATPase, and NCC expression were similar in D2RPT‐/‐ and D2RPT+/+ but NKCC2 was lower (100±20 vs 710±10; P<0.05) in D2RPT‐/‐ than in D2RPT+/+. However, the increased BP in D2RPT‐/‐ on LS cannot be explained by changes in renal expression of sodium exchanger/transporter/pump but may be related to the increase in renal inflammation and fibrosis. These results may have significant clinical implications since in humans, the presence of D2R variants, DRD2rs6276 and rs6277, which decrease D2R protein/function, is associated with an increase in BP on LS diet, a case of inverse salt sensitivity.