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Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors

Florian Gembardt^*,, Silvia Heringer-Walther^*, Joep H.M. van Esch, Anja Sterner-Kock, Richard van Veghel, Thu H. Le, Ingrid M. Garrelds, Thomas M. Coffman, A.H. Jan Danser, Heinz-Peter Schultheiss^* and Thomas Walther^*,¶,1

^* Department of Cardiology, Charité Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany;

Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands;

Institute for Veterinary Pathology, Free University, Berlin, Germany;

Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA; and

^¶ Department of Biomedical Sciences, Hull York Medical School, University of Hull, UK

¹Correspondence: Hull York Medical School, University of Hull, Wolfson Bldg., Cottingham Rd., Hull HU6 7RX, UK. E-mail: thomas.walther{at}hyms.ac.uk

Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT₁) and type 2 (AT₂). In rodents, two AT₁ subtypes were identified (AT_1a and AT_1b). To determine receptor-specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT₁ subtypes. All combinations lacking AT_1a were distinguished by reduced heart rate. AT_1a deletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT_1b and/or AT₂ had no effect. However, the additional lack of AT_1b in AT_1a-deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the renin-angiotensin system and to search for angiotensin II effects independent of AT₁ and AT₂.—Gembardt, F., Heringer-Walther, S., van Esch, J. H. M., Sterner-Kock, A., van Veghel, R., Le, T. H., Garrelds, I. M., Coffman, T. M., Danser, A. H. J., Schultheiss, H.-P., and Walther, T. Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors.

Key Words: hemodynamics • receptor genes • transgenic mice • transmembrane-spanning receptors