In recent years, research from our laboratory and others has shown that innate and adaptive immunity play critical roles in the genesis of hypertension. The major hypothesis of this project is that the central nervous system coordinates actions of dendritic cells (DCs) and T cells, which in turn affect the vasculature and kidney to raise blood pressure. We have also discovered a novel role of isoketal-protein adducts in hypertension. These oxidatively modified proteins accumulate in DCs, lead to DC activation and seem to act as neoantigens. In a recent study, we have also shown that a major site of DC and T cell activation in hypertension is the kidney. These findings are extremely novel, because they show a new role of DCs in hypertension, and we plan to gain further insight into activation of these cells by hypertensive stimuli in vivo. We will interrupt sympathetic outflow by deleting the NADPH oxidase subunit p22phox in the rostroventral lateral medulla using cre-lox technology and will prevent the central actions of angiotensin II by deleting the AT1 receptor (AT1R) in circumventricular organs. We will also examine the direct effect of angiotensin II on DCs by deleting the AT1R in DCs, again using Cre-Lox approaches. The impact of these interventions will be monitored by examining DC isoketal-adduct formation and superoxide production in conjunction with Core A.
In aim 2, we will employ novel mice we have made that have soluble forms of class 1 major histocompatibility complexes (MHC1). DCs from these mice shed large quantities of MHC1 and we have adopted methods to harvest isoketal-adducted peptides from these for proteomic analysis. In collaboration with project 3, we will examine the ability of specific isoketal-adducted peptides identified in aim 2 to drive proliferation of hypertension-specific T cell hybridomas.
In aim 3, we will examine the role of memory T cells in responses to repeated hypertensive challenges. Our preliminary data show that these have a critical role in modulating salt-sensitive hypertension. A model developed in conjunction with project 3 will be employed. Preliminary data indicate that these repeated challenges promote renal accumulation of effector memory T cells (TEM cells) that produce large amounts of IL- 17A and IFN-?. We also find that TEM cells accumulate in the bone marrow of hypertensive mice, and will determine the role of these in responding to repeated hypertensive stimuli, and how the sympathetic nervous system modulates their trafficking and activation. An important aspect of this aim will be to determine if memory T cells of humans with either hypertension or pre-hypertension have epigenetic alterations that predispose to inflammatory cytokine production. These experiments will employ a novel ATAC-seq technology, performed in collaboration with Drs. Weyand and Goronzy in project 2, to map the epigenetic landscape of T cell subsets. Overall, these studies promise to further our understanding of hypertension and provide new therapeutic options for this common and difficult to treat disease.
The end-organ damage caused by hypertension is in large part mediated by inflammation, which in turn alters blood vessel and kidney function. This project will define unique molecular mechanisms underlying activation of immune/inflammatory cells in hypertension and in doing so will identify novel strategies for treatment of this devastating disease.
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| Norlander, Allison E; Madhur, Meena S; Harrison, David G (2018) The immunology of hypertension. J Exp Med 215:21-33 |
| Uribe, Jorge A; Aggarwal, Ishita; Witthayaweerasak, Juthamat et al. (2018) Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis. J Neuroophthalmol 38:17-23 |
| Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2018) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol 105:118-127 |
| Goronzy, Jörg J; Hu, Bin; Kim, Chulwoo et al. (2018) Epigenetics of T cell aging. J Leukoc Biol 104:691-699 |
| Weyand, Cornelia M; Berry, Gerald J; Goronzy, Jörg J (2018) The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. J Leukoc Biol 103:565-575 |
| Eriguchi, Masahiro; Bernstein, Ellen A; Veiras, Luciana C et al. (2018) The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease. J Am Soc Nephrol 29:2546-2561 |
| Watanabe, Ryu; Maeda, Toshihisa; Zhang, Hui et al. (2018) MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res 123:700-715 |
| Weyand, Cornelia M; Shen, Yi; Goronzy, Jorg J (2018) Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med 125:36-43 |
| Bernstein, Kenneth E; Khan, Zakir; Giani, Jorge F et al. (2018) Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol 14:325-336 |
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