The Renal Mechanisms Involved In The Response To Salt Intake Are Sex Related In Mice

Dopamine receptor D2 (Drd2) plays an important role in maintaining normal blood pressure (BP) by regulating renal Na + transport. Knockdown of Drd2 in renal proximal tubule cells (RPTCs) may affect BP and Na + transport differently between male and female mice. We studied the effects of Drd2 in RPTCs of the mouse kidney by generating Drd2 fl/fl , P SGLT2 ::Cre + mice (D2R PT-/- ) that lack D2R only in RPTC and Drd2 fl/fl , P SGLT2 ::Cre - (D2R PT+/+ ) mice that do not have the deletion. The study was performed in male and female mice on normal (0.8% NaCl, NS) and low (0.025-0.05% NaCl; LS) salt diets. On NS diet mean arterial pressures (MAPs, mm Hg), measured under pentobarbital anesthesia, were similar in male D2R PT+/+ (86.38±2.20, n=13) and D2R PT-/- (91.58±1.63, n=19) and female D2R PT+/+ (82.57±2.33, n=14) and D2R PT-/- (85.17±6.09, n=12) mice . By contrast, in D2R PT-/- mice, LS diet similarly increased MAP in male (108.11±7.04 (n=10) and female (103.00±9.98 (n=5) mice. The renal NHE3 protein expression (%) was higher in male than female mice (D2R PT+/+ : 100±4 (male) vs 30±15 (female); n=8/group; P<0.0001; D2R PT-/- 117±10 (male) vs 44±16 (female); n=8/group; P<0.02 ). However, NKCC expression (%) was higher in female than male D2R PT+/+ (788±10 (female) vs 100±4 (male), n=8/group; P<0.01); there was no difference between D2R PT-/- male and female mice. The expressions of Na + -K + /ATPase, NCC, SGLT2, and ENaC were similar in males and females of the two genotypes. These findings suggest that on LS diet D2R knockdown in the RPTC increases BP in both male and female mice but the changes in NHE3 and NKCC expressions are different between male and female mice. These results suggests that the MAP response to salt intake is not affected by sex but the renal mechanisms involved are sex-related.