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. 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.

[1]  C. Semenkovich,et al.  Absence of Peroxisome Proliferator-Activated Receptor-&agr; Abolishes Hypertension and Attenuates Atherosclerosis in the Tsukuba Hypertensive Mouse , 2007, Hypertension.

[2]  D. Harrison,et al.  Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction , 2007, The Journal of experimental medicine.

[3]  J. Shendure,et al.  A Molecular Pathway Including Id2, Tbx5, and Nkx2-5 Required for Cardiac Conduction System Development , 2007, Cell.

[4]  A. Takakura,et al.  Human T and natural killer cells possess a functional renin-angiotensin system: further mechanisms of angiotensin II-induced inflammation. , 2007, Journal of the American Society of Nephrology : JASN.

[5]  C. Lau,et al.  Prevalence, Awareness, Treatment, and Control of Hypertension Among United States Adults 1999–2004 , 2007, Hypertension.

[6]  B. Rodriguez-Iturbe,et al.  Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. , 2006, Journal of the American Society of Nephrology : JASN.

[7]  Phillip Ruiz,et al.  Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney , 2006, Proceedings of the National Academy of Sciences.

[8]  A. Goldrath,et al.  Transcriptional regulator Id2 mediates CD8+ T cell immunity , 2006, Nature Immunology.

[9]  M. Bennett,et al.  Vascular smooth muscle cell senescence in atherosclerosis. , 2006, Cardiovascular research.

[10]  A. Kribben,et al.  CCL19-IgG prevents allograft rejection by impairment of immune cell trafficking. , 2006, Journal of the American Society of Nephrology : JASN.

[11]  P. Kirkpatrick,et al.  Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis: Effects of Telomerase and Oxidative Stress , 2006, Circulation research.

[12]  A. Lasaridis,et al.  Actions of peroxisome proliferator-activated receptors-gamma agonists explaining a possible blood pressure-lowering effect. , 2006, American journal of hypertension.

[13]  H. Kobori,et al.  Molecular aspects of the renal renin-angiotensin system , 2006 .

[14]  R. D. Manning,et al.  Immune Suppression Prevents Renal Damage and Dysfunction and Reduces Arterial Pressure in Salt‐Sensitive Hypertension , 2006, American journal of physiology. Heart and circulatory physiology.

[15]  Marta Ruiz-Ortega,et al.  Renal and vascular hypertension-induced inflammation: role of angiotensin II , 2006, Current opinion in nephrology and hypertension.

[16]  B. Staels,et al.  PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. , 2005, The Journal of clinical investigation.

[17]  M. Wellner,et al.  Complement Activation in Angiotensin II–Induced Organ Damage , 2005, Circulation research.

[18]  A. Iavarone,et al.  Id family of helix-loop-helix proteins in cancer , 2005, Nature Reviews Cancer.

[19]  Hyung-Suk Kim,et al.  Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. , 2005, The Journal of clinical investigation.

[20]  M. Wellner,et al.  Cardiac gene expression profile in rats with terminal heart failure and cachexia. , 2005, Physiological genomics.

[21]  Y. Yokota,et al.  Id2 haploinsufficiency in mice leads to congenital hydronephrosis resembling that in humans , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[22]  A. Daugherty,et al.  Depletion of Natural Killer Cell Function Decreases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[23]  S. Mathur,et al.  PPAR&ggr; Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice , 2004, Hypertension.

[24]  S. Ohtsuka,et al.  Amlodipine Improves Vascular Function in Patients With Moderate to Severe Hypertension , 2003, Journal of cardiovascular pharmacology.

[25]  R. Benezra,et al.  Id proteins in development, cell cycle and cancer. , 2003, Trends in cell biology.

[26]  G. Owens,et al.  Smooth Muscle &agr;-Actin Gene Requires Two E-Boxes for Proper Expression In Vivo and Is a Target of Class I Basic Helix-Loop-Helix Proteins , 2003, Circulation research.

[27]  S. Rose-John,et al.  Transcriptional profiling identifies Id2 function in dendritic cell development , 2003, Nature Immunology.

[28]  M. Zenke,et al.  Immunosuppressive treatment protects against angiotensin II-induced renal damage. , 2002, The American journal of pathology.

[29]  Y. Tomino,et al.  Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway1 , 2002, The Journal of Immunology.

[30]  D. Ganten,et al.  Reduced hypertension-induced end-organ damage in mice lacking cardiac and renal angiotensinogen synthesis , 2002, Journal of Molecular Medicine.

[31]  C. McNamara,et al.  Contribution of the Helix-Loop-Helix Factor Id2 to Regulation of Vascular Smooth Muscle Cell Proliferation* , 2002, The Journal of Biological Chemistry.

[32]  S. Rafii,et al.  The Id proteins and angiogenesis , 2001, Oncogene.

[33]  E. Schiffrin.  Effects of antihypertensive drugs on vascular remodeling: do they predict outcome in response to antihypertensive therapy? , 2001, Current opinion in nephrology and hypertension.

[34]  D. Ganten,et al.  Aspirin inhibits NF‐κB and protects from angiotensin II‐induced organ damage , 2001 .

[35]  J. Blanco,et al.  Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-κB and AP-1 in the Kidney : Role of AT1 and AT2 Receptors , 2001 .

[36]  R. Plehm,et al.  Long‐term blood pressure telemetry in AT2 receptor‐disrupted mice , 2000, Journal of hypertension.

[37]  W. Hsueh,et al.  Expression and Function of PPARγ in Rat and Human Vascular Smooth Muscle Cells , 2000 .

[38]  P. Mannon,et al.  Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. , 1999, The Journal of clinical investigation.

[39]  Ahmed Mansouri,et al.  Development of peripheral lymphoid organs and natural killer cells depends on the helix–loop–helix inhibitor Id2 , 1999, Nature.

[40]  T. Buchanan,et al.  Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. , 1995, The Journal of clinical investigation.

[41]  F. Luft,et al.  Platelet-derived growth factor and angiotensin II induce different spatial distribution of protein kinase C-alpha and -beta in vascular smooth muscle cells. , 1994, Hypertension.

[42]  K. Griendling,et al.  Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. , 2007, American journal of physiology. Cell physiology.

[43]  D. Warburton,et al.  BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[44]  T. Nakahata,et al.  TH2 dominance and defective development of a CD8+ dendritic cell subset in Id2-deficient mice. , 2003, The Journal of allergy and clinical immunology.

[45]  Y. E. Chen,et al.  Thiazolidinediones, a class of anti-diabetic drugs, inhibit Id2 expression through a PPARγ-independent pathway in human aortic smooth muscle cells , 2003, Cellular and Molecular Life Sciences CMLS.

[46]  D. Ganten,et al.  Aspirin inhibits NF-kappaB and protects from angiotensin II-induced organ damage. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[47]  W. Hsueh,et al.  Expression and function of PPARgamma in rat and human vascular smooth muscle cells. , 2000, Circulation.