Conditional knockout of collecting duct bradykinin B₂ receptors exacerbates angiotensin II-induced hypertension during high salt intake

Abstract

We elucidated the role of collecting duct kinin B₂ 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 UB^{Bdkrb2−/−} 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 (1000 ng/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 ± 3 mmHg) and UB^{Bdkrb2−/−} mice (120 ± 2 to 153 ± 2 mmHg). The development of ANG II-induced hypertension was exacerbated by 4%HS in both control (125 ± 3 to 164 ± 5 mmHg) and UB^{Bdkrb2−/−} mice (124 ± 2 to 162 ± 3 mmHg) during 2 weeks. Interestingly, 8%HS caused a more profound and earlier ANG II-induced hypertension in UB^{Bdkrb2−/−} (129 ± 2 to 166 ± 3 mmHg) as compared to control (128 ± 2 to 158 ± 2 mmHg) 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.

• Angiotensin II
• bradykinin receptor
• collecting duct
• Cre recombinase
• high salt diet
• hypertension
• kallikrein–kinin system

Declaration of interest

This study was principally supported by grant No. NT 14011-3/2013 awarded by the Internal Grant Agency of the Ministry of Health to L.K.

Institute for Clinical and Experimental Medicine (IKEM) is recipient of the project of the Ministry of Health of the Czech Republic for the development of research organization 00023001 (institutional support). The Center for Experimental Medicine (IKEM) received financial support from the European Commission within the Operational Program Prague–Competitiveness; project “Rozvoj infraskruktury PEM” (#CZ.2.16/3.1.00/28025). Work in SED laboratory is supported by a National Institutes of Health grant DK56264.

Supplementary material available online

Supplementary Figure 1.