Conditional knockout of collecting duct bradykinin B-2 receptors exacerbates angiotensin II-induced hypertension during high salt intake
Abstract
We elucidated the role of collecting duct kinin B-2 receptor (B2R) in the development of salt-sensitivity and angiotensin II (ANG II)-induced hypertension. To this end, we used a Cre-Lox recombination strategy to generate mice lacking Bdkrb2 gene for B2R in the collecting duct (Hoxb7-Cre(tg/+):Bdkrb2(flox/flox)).
In 3 groups of control (Bdkrb2(flox/flox)) and 3 groups of UBBdkrb2-/- mice, systolic blood pressure (SBP) responses to high salt intake (4 or 8% NaCl; HS) were monitored by radiotelemetry in comparison with standard salt diet (0.4% NaCl) prior to and during subcutaneous ANG II infusion (1000ng/min/kg) via osmotic minipumps. High salt intakes alone for 2 weeks did not alter SBP in either strain.
ANG II significantly increased SBP equally in control (121 +/- 2 to 156 +/- 3mmHg) and UBBdkrb2-/- mice (120 +/- 2 to 153 +/- 2mmHg). The development of ANG II-induced hypertension was exacerbated by 4%HS in both control (125 +/- 3 to 164 +/- 5mmHg) and UBBdkrb2-/- mice (124 +/- 2 to 162 +/- 3mmHg) during 2 weeks.
Interestingly, 8%HS caused a more profound and earlier ANG II-induced hypertension in UBBdkrb2-/- (129 +/- 2 to 166 +/- 3mmHg) as compared to control (128 +/- 2 to 158 +/- 2mmHg) and it was accompanied by body weight loss and increased mortality. In conclusion, targeted inactivation of B2R in the renal collecting duct does not cause salt-sensitivity; however, collecting duct B2R attenuates the hypertensive actions of ANG II under conditions of very high salt intake.