Novel role for inhibitor of differentiation 2 in the genesis of angiotensin II-induced hypertension


  • P. Gratze
  • R. Dechend
  • C. Stocker
  • J.K. Park
  • S. Feldt
  • E. Shagdarsuren
  • M. Wellner
  • F. Gueler
  • S. Rong
  • V. Gross
  • M. Obst
  • R. Plehm
  • N. Alenina
  • A. Zenclussen
  • J. Titze
  • K. Small
  • Y. Yokota
  • M. Zenke
  • F.C. Luft
  • D.N. Mueller


  • Circulation


  • Circulation 117 (20): 2645-2656


  • 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.