Published online before print May 12, 2008, doi: 10.1161/CIRCULATIONAHA.107.760116
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(Circulation. 2008;117:2645-2656.)
© 2008 American Heart Association, Inc.
Hypertension |
Novel Role for Inhibitor of Differentiation 2 in the Genesis of Angiotensin II–Induced Hypertension
From the Medical Faculty of the Charité (P.G., R.D., C.S., S.F., M.W., F.C.L., D.N.M.), Experimental and Clinical Research Center, Franz Volhard Clinic, and HELIOS Clinic, Berlin, Germany; Medical School of Hannover (J.K.-P., F.G., S.R.), Hannover, Germany; Max Delbrück Center for Molecular Medicine (V.G., M.O., R.P., N.A., F.C.L., D.N.M.), Berlin-Buch, Germany; Institute for Molecular Cardiovascular Research (E.S.), RWTH Aachen University, Aachen, Germany; Institute of Medical Immunology (A.Z.), Medical Faculty of the Charité, Berlin, Germany; Friedrich Alexander University (J.T.), Erlangen, Nürnberg, Germany; Merck & Co Inc (K.S.), Research Laboratories, Rahway, NJ; Department of Molecular Genetics (Y.Y.), School of Medicine, University of Fukui, Fukui, Japan; and Institute for Biomedical Engineering (M.Z.), Aachen University Medical School, Aachen, Germany.
Correspondence to Dominik N. Muller, PhD, Max Delbruck Center and Clinical and Experimental Research Center, Lindenberger Weg 80, 13125 Berlin, Germany. E-mail dominik.mueller{at}mdc-berlin.de
Received December 12, 2007; accepted March 12, 2008.
Background— Angiotensin (Ang) II–induced target-organ damage involves innate and acquired immunity. Mice deficient for the helix-loop-helix transcription factor inhibitor of differentiation (Id2–/–) lack Langerhans and splenic CD8a+ dendritic cells, have reduced natural killer cells, and have altered CD8 T-cell memory. We tested the hypothesis that an alteration in the number and quality of circulating blood cells caused by Id2 deletion would ameliorate Ang II–induced target-organ damage.
Methods and Results— We used gene-deleted and transgenic mice. We conducted kidney and bone marrow transplants. In contrast to Ang II–infused Id2+/–, Id2–/– mice infused with Ang II remained normotensive and failed to develop albuminuria or renal damage. Bone marrow transplant of Id2+/– bone marrow to Id2–/– mice did not restore the blunted blood pressure response to Ang II. Transplantation of Id2–/– kidneys to Id2+/– mice also could not prevent Ang II–induced hypertension and renal damage. We verified the Ang II resistance in Id2–/– mice in a model of local tissue Ang II production by crossing hypertensive mice transgenic for rat angiotensinogen with Id2–/– or Id2+/– mice. Angiotensinogen-transgenic Id2+/– mice developed hypertension, albuminuria, and renal injury, whereas angiotensinogen-transgenic Id2–/– mice did not. We also found that vascular smooth muscle cells from Id2–/– mice showed an antisenescence phenotype.
Conclusions— Our bone marrow and kidney transplant experiments suggest that alterations in circulating immune cells or Id2 in the kidney are not responsible for Ang II resistance. The present studies identify a previously undefined role for Id2 in the pathogenesis of Ang II–induced hypertension.
CLINICAL PERSPECTIVE
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Clinical Summaries
Circulation 2008 117: 2567-2569.[Full Text]