Research in our laboratory in the last several years has shown that T cells are essential for the development of hypertension. We have found that RAG-1"'" mice, which lack both T and B lymphocytes, develop very blunted hypertensive responses to either chronic low-dose angiotensin II infusion or to DOCA-salt challenge. Adoptive transfer of T, but not B, lymphocytes completely restores the pressor responses to these stimuli. We have found that angiotensin II stimulates a modest increase in T cell expression of the tissue homing markers CCR5 and CD44, which are characteristic of effector T cells. We believe this is important for the genesis of hypertension because we find a striking increase in infiltration of T cells into the perivascular fat around both the aorta and mesenteric vessels in hypertensive mice. The overall hypothesis to be tested in this project is that T cell activation via diverse mechanisms markedly augments the hypertensive response to challenges that normally have no or only minimal effect on blood pressure and that therapy with immunomodulatory agents is a promising approach for treatment of hypertension.
In aim 1, we will test this hypothesis by immunizing mice with antigen from the dental pathogen Porphyromonas gingivalis (P. gingivalis) and then present hypertensive stimuli including angiotensin II, DOCA-salt hypertension and a central stimulus for hypertension. Stimuli that promote THi and TH2 cell polarization will be employed. Preliminary data indicate that previous immunization of mice leads to severe hypertension upon challenge with a low dose of angiotensin II that normally causes minimal increase in blood pressure. An important proinflammatory cytokine, independent of TH1/TH2 cytokines, is IL-17, which we find to be present in the endothelium and perivascular tissues of angiotensin IItreated mice. Our preliminary data in IL17''" mice indicate that it contributes to angiotensin ll-induced hypertension. We will examine the role of IL-17 in the response to angiotensin II and DOCA salt hypertension in naive mice and in mice after immunological stimulation with P. gingivalis lysate by studying IL-17 deficient mice. In preliminary data, we have found that angiotensin II stimulates an increase in renal medullary superoxide levels and a concomitant decrease in renal nitric oxide, and that this is absent in mice lacking T and B cells. We also find that RAG1'''mice exhibit a striking diuresis and natriuresis when challenged with angiotensin II.
In aim 3, we will examine the role of T cells on these renal parameters during angiotensin llinduced hypertension and determine if pre-immunization enhances these effects. Finally in aim 4, we will test the potential for two therapies that can affect either T cell activation or tissue homing to prevent hypertension. In summary, these studies will provide new information regarding the inflammatory processes underlying hypertension and promise to provide new treatment strategies for this common disease
|Brown, David I; Lassègue, Bernard; Lee, Minyoung et al. (2014) Poldip2 knockout results in perinatal lethality, reduced cellular growth and increased autophagy of mouse embryonic fibroblasts. PLoS One 9:e96657|
|Kumar, Sandeep; Kim, Chan Woo; Simmons, Rachel D et al. (2014) Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol 34:2206-16|
|Lyle, Alicia N; Remus, Ebony W; Fan, Aaron E et al. (2014) Hydrogen peroxide regulates osteopontin expression through activation of transcriptional and translational pathways. J Biol Chem 289:275-85|
|Tarbell, John M; Shi, Zhong-Dong; Dunn, Jessilyn et al. (2014) Fluid Mechanics, Arterial Disease, and Gene Expression. Annu Rev Fluid Mech 46:591-614|
|San Martin, Alejandra; Griendling, Kathy K (2014) NADPH oxidases: progress and opportunities. Antioxid Redox Signal 20:2692-4|
|Wu, Jing; Thabet, Salim R; Kirabo, Annet et al. (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616-25|
|Dunn, Jessilyn; Qiu, Haiwei; Kim, Soyeon et al. (2014) Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J Clin Invest 124:3187-99|
|Vukelic, Sasa; Griendling, Kathy K (2014) Angiotensin II, from vasoconstrictor to growth factor: a paradigm shift. Circ Res 114:754-7|
|Kirabo, Annet; Fontana, Vanessa; de Faria, Ana P C et al. (2014) DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest 124:4642-56|
|Trott, Daniel W; Thabet, Salim R; Kirabo, Annet et al. (2014) Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64:1108-15|
Showing the most recent 10 out of 41 publications