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


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.
Gratze
Petra
P
Medical Faculty of the Charité, Experimental and Clinical Research Center, Franz Volhard Clinic, Berlin, Germany.
Dechend
Ralf
R
Stocker
Carolin
C
Park
Joon-Keun
JK
Feldt
Sandra
S
Shagdarsuren
Erdenechimeg
E
Wellner
Maren
M
Gueler
Faikah
F
Rong
Song
S
Gross
Volkmar
V
Obst
Michael
M
Plehm
Ralph
R
Alenina
Natalia
N
Zenclussen
Ana
A
Titze
Jens
J
Small
Kersten
K
Yokota
Yoshifumi
Y
Zenke
Martin
M
Luft
Friedrich C
FC
Muller
Dominik N
DN
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001773:Blood Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology*; D007107:Immune System / Q000166:cytology; D051797:Inhibitor of Differentiation Protein 2 / Q000172:deficiency / Q000502:physiology*; D016030:Kidney Transplantation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
D051797:Inhibitor of Differentiation Protein 2; D000804:Angiotensin II