Portal de Periódicos da CAPES

Interactions Between the Immune and the Renin–Angiotensin Systems in Hypertension

2016; Lippincott Williams & Wilkins; Volume: 68; Issue: 2 Linguagem: Inglês

10.1161/hypertensionaha.116.06591

1524-4563

Nathan P. Rudemiller, Steven D. Crowley,

Asthma and respiratory diseases

HomeHypertensionVol. 68, No. 2Interactions Between the Immune and the Renin–Angiotensin Systems in Hypertension Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBInteractions Between the Immune and the Renin–Angiotensin Systems in Hypertension Nathan P. Rudemiller and Steven D. Crowley Nathan P. RudemillerNathan P. Rudemiller From the Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, NC. and Steven D. CrowleySteven D. Crowley From the Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, NC. Originally published27 Jun 2016https://doi.org/10.1161/HYPERTENSIONAHA.116.06591Hypertension. 2016;68:289–296Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 IntroductionThe renin–angiotensin system (RAS) is an essential regulator of blood pressure homeostasis. The primary effector molecule of the RAS is angiotensin (Ang) II, an 8-amino acid peptide that initiates tissue-specific processes via binding to the type 1 or 2 angiotensin II receptors (AT1 or AT2). The AT1 receptor is a G-protein–coupled receptor expressed in most tissues throughout the body. Although the rodent expresses 2 AT1 receptor isoforms, AT1A and AT1B, the closest functional homolog to the human AT1 receptor in most rodent tissues is AT1A. The most widely appreciated functions of Ang II signaling via the AT1 receptor are to augment global vascular tone and to promote sodium retention in the kidney, thus playing a crucial role in acute and long-term maintenance of blood pressure.1,2 Ang II elicits these effects by increasing the contractility of vascular smooth muscle, promoting the release of aldosterone from the adrenal cortex, and directly increasing the expression or activity of solute transporters in the renal tubules that promote sodium reabsorption. As such, blockade of the RAS has been a mainstay in the treatment for hypertension and its complications, including cardiovascular and kidney disease.2,3 Although the cause of essential hypertension is unclear, inhibition of the RAS is effective in reducing blood pressure in a wide variety of patients, which suggests that inappropriate RAS activation is common in the pathogenesis of this idiopathic condition. Global RAS inhibitors ameliorate hypertension by blocking the production of Ang II or by preventing activation of the AT1 receptor. These medications are global inhibitors in the sense that they disrupt AT1 receptor signaling concomitantly in all tissues.The ongoing effort to uncover novel pathogenic mechanisms of hypertension has revealed a significant role for the immune system.4 Although augmentation of hypertension and associated organ damage by the immune system has been appreciated for >5 decades, intense experimental investigation of this phenomenon commenced ≈15 years ago. Over this period, leukocytes have been shown to modulate the hypertensive response in a plethora of experimental models.5 Immune cells infiltrate cardiovascular control centers that regulate blood pressure, such as the kidney, blood vessels, and brain. There they produce factors that promote local inflammation and sodium retention and mediate tissue injury, ultimately leading to elevated blood pressure. Human data on this phenomenon are currently sparse, yet indicative of an immune-related component to hypertension.6,7The dominant angiotensin receptor expressed on immune cells is the AT1 receptor, and their inflammatory functions are altered by its activation.8–10 Furthermore, activation of the AT1 receptor on distinct cell populations within the immune compartment has effects on blood pressure and renal damage that contrast starkly with AT1 receptor actions in the kidney and vasculature.11 These emerging data suggest that global inhibition of the RAS may not be optimal in the treatment of hypertension, and that understanding cell-specific actions of the AT1 receptor in the setting of hypertension may guide novel therapeutics that manipulate the RAS via tissue-specific strategies. The aim of this review is to describe the interplay between the RAS and immune system in hypertension.Immune System, the AT1 Receptor, and HypertensionThe immune system is composed of 2 arms: the innate immune system, which mounts a rapid, nonspecific response to a wide array of pathogens, and the adaptive immune system, which executes an antigen-specific response subsequent to the innate response. Myeloid cells largely comprise the innate arm and trigger engagement of the adaptive immune response. By contrast, lymphoid cells contribute primarily to adaptive immunity. The myeloid compartment contains a vast collection of immune cells, including monocytes, macrophages, and dendritic cells, with varying capacities to fight invading pathogens, whereas the lymphoid compartment is largely comprised of 2 cell types: T and B lymphocytes.A link between the immune system and the hypertension has long been recognized because inflammatory cells were shown to traffick to organs that regulate blood pressure decades ago. For example, Sommers et al12 recognized a positive correlation between lymphocyte aggregation and the degree of arteriolar nephrosclerosis in kidney biopsies from hypertensive patients. Experimentally in 1967, monocytes were shown to accumulate in the aortic intima as early as 4 hours after hypertension was induced in rats by aortic constriction.13 Moreover in 1969, studies of kidney glomeruli in the hypertensive rat revealed a marked accrual of monocytes compared with normotensive controls.14 Olsen15 then showed that transfer of splenocytes from a hypertensive rat could recapitulate hypertension in a normotensive rat. Inversely, Svendsen16 reported that athymic mice were protected from deoxycorticosterone acetate hypertension. Since these initial observations and in several hypertensive models, immune cells have been implicated in vascular injury, kidney damage, and inappropriate sodium retention —all pathological amplifiers of blood pressure elevation. Moreover, hypertension emerges in autoimmune disorders such as systemic lupus erythematosus, and blocking inflammatory responses in systemic lupus erythematosus can dramatically reduce blood pressure.17,18As RAS stimulation and immune system activation both contribute to the pathogenesis of hypertension, several investigators have explored whether ligation of AT1 receptors on immune cells can modulate blood pressure or can target organ damage in hypertension. Bone marrow transplant (BMT) experiments, utilizing donor mice that are genetically deficient of the dominant rodent AT1 receptor isoform, AT1A (Agtr1a−/−), have demonstrated context-specific effects of the immune AT1 receptor in hypertension and cardiovascular disease. One such study used the Tsukuba mouse, which carries the human renin and angiotensinogen transgenes. This mouse is a model of RAS-mediated, persistent hypertension and atherosclerosis precipitated by an atherogenic diet.19 Tsukuba mice underwent BMT using Agtr1a−/− or Agtr1a+/+ donors and were placed on the atherogenic diet 6 weeks later. The level of hypertension was similar between Tsukuba mice receiving Agtr1a−/− or Agtr1a+/+ bone marrow (BM) cells, but the absence of the AT1A receptor on BM cells increased the severity of atherosclerotic lesions in the aorta.20 Our laboratory utilized BMT to explore the actions of AT1A receptors on immune cells in Ang II–induced hypertension.21 Although the absence of AT1A on bone marrow cells did not affect baseline blood pressure, the mice that received Atgr1a−/− BM cells had an augmented hypertensive response to chronic Ang II infusion compared with mice receiving Atgr1a+/+ BM cells, along with exaggerated accumulation of macrophages and T cells in the hypertensive kidney. Together, these studies pointed to a protective effect of the immune cell AT1 receptor in hypertension and associated complications.AT1A receptors on bone marrow–derived cells can similarly ameliorate kidney damage even in the absence of hypertension. For example, in an RAS-dependent model of kidney fibrosis induced by unilateral ureteral obstruction, transplantation of Agtr1a−/− bone marrow into wild-type (WT) mice induced greater renal expression of profibrotic genes and more severe interstitial fibrosis when compared with WT transplant controls.22 Ma et al23 similarly found that AT1A receptor–deficient mice had exaggerated obesity-dependent kidney damage, attributed to enhanced proinflammatory macrophage responses. By contrast, in the apolipoprotein E–deficient mouse model of atherosclerosis, reconstitution with Agtr1a−/− BM cells significantly blunted the formation of atherosclerotic lesions in the aorta and kidney,24,25 consistent with pathogenic actions of AT1 receptors on bone marrow–derived cells.We speculate that these conflicting actions of the immune cell AT1 receptor in hypertension and cardiovascular disease may relate to the specific subsets of immune cells involved in mediating tissue pathology in the respective models. To this point, a variety of immune cells have been implicated in regulating blood pressure and the extent of tissue injury in hypertension. These include both pro- and anti-inflammatory subsets that are proposed to have deleterious and salutary functions, respectively, in target organ pathology.26 Because the BMT studies mentioned above abrogated AT1A receptor signaling on all immune cell populations, more precise approaches are required to determine in vivo how the AT1 receptor signaling influences the function of particular immune cell subsets in the setting of hypertension. We have pursued cell-specific, conditional deletion strategies to confront this problem, and others have utilized adoptive transfer approaches. Below we will review the current understanding of how particular myeloid and lymphoid subsets participate in the pathogenesis of hypertension and discuss recent findings on the effects of AT1A receptor activation on immune cell function in this setting. We will focus predominantly on monocytes, macrophages, and T cells, as the majority of studies in the field of hypertension to date have generated data on these immune cell subsets.Monocytes/Macrophages, the AT1 Receptor, and HypertensionMonocytes are a subset of circulating myeloid cells that originate in the bone marrow and play a pivotal role in immunity during homeostasis and disease.27 The stratification of murine monocytes into functionally distinct populations is continually revised, but one schema parses monocytes based on their expression of the surface marker Ly6C.28 Robust expression of Ly6C (Ly6Chi) designates a proinflammatory subset of monocytes that are heavily recruited to sites of inflammation and produce reactive oxygen species (ROS), interleukin 1β (IL-1β), and tumor necrosis factor (TNF)-α. The human counterpart is the proinflammatory CD14hiCD16− monocyte population. Minimal or no expression of Ly6C (Ly6Clo) identifies an anti-inflammatory subset of murine monocytes said to patrol the luminal endothelium under homeostatic conditions to rapidly detect vascular insult.29 In humans, these patrolling monocytes are identified by CD14loCD16hi double positivity. Besides their direct inflammatory capacity, monocytes have long been thought to maintain appropriate levels of resident tissue macrophages via differentiation although recent evidence suggests a more complex relationship between circulating and resident tissue myeloid cell pools.30,31Macrophages are resident tissue phagocytes that play a critical role in innate immunity. Apart from their phagocytic capacity, macrophages release inflammatory mediators and recruit and program other immune cells. In 1 paradigm, macrophages are divided into 2 subsets, M1 and M2.31 M1, or classically activated, macrophages are proinflammatory and, like their Ly6Chi monocyte precursors, release the cytokines IL-1β and TNF and produce ROS. M2, or alternatively activated, macrophages display an anti-inflammatory phenotype, are involved in tissue repair, and elaborate regulatory cytokines such as IL-10 and transforming growth factor β.32 Although monocytes and macrophages are essential for proper immune homeostasis, their dysregulation contributes to diverse pathologies ranging from classic autoimmune diseases to hypertension.4,33Both experimental and clinical data point to a key role for monocytes and macrophages in hypertension. The monocyte chemokine CCL2 (monocyte chemoattractant protein-1) is highly expressed in the kidney and vasculature during hypertension,34,35 leading to the infiltration of monocytes expressing CCR2, the receptor for monocyte chemoattractant protein-1, into these tissues.36,37 Accordingly, depletion of LysM-expressing monocytes blunts the chronic hypertensive response to Ang II,38 whereas inhibition of monocyte chemoattractant protein-1 or CCR2 blunts renal and aortic myeloid cell invasion and attenuates both hypertension and consequent tissue injury.37,39 Within the target organ, monocytes and macrophages instigate and sustain inflammation that causes tissue damage and augments blood pressure elevation. In the Ang II hypertension model, proinflammatory monocyte- and macrophage-expressing M1 markers infiltrate the aorta by day 7,40 whereas later, at day 14, these aortic macrophages favor an M2 phenotype featuring CD206 expression.34 Whether this phenotypic shift reflects temporal plasticity of the initial M1 macrophage infiltrate or its replacement by M2 macrophages is unclear, but there is precedent for plasticity of macrophages in tissue injury and repair.32,41 In clinical hypertension, histological analysis of postmortem kidneys shows a significant increase in cortical density of CD68+ monocytes/macrophages compared with normotensive controls.42 Moreover, circulating monocytes from hypertensive patients have an enhanced proinflammatory phenotype when stimulated ex vivo,43 and circulating levels of inflammatory chemokines are elevated in hypertensive patients.44–46Proinflammatory monocytes/macrophages have the capacity to potentiate hypertension through multiple mechanisms. As a part of the innate immune response, myeloid cells can promote remodeling in the vasculature and epithelial cell injury in the kidney, prompting endothelial dysfunction and impairing appropriate excretion of sodium in the setting of hypertension. However, even in the absence of renal injury, M1 macrophages can promote sodium retention in the kidney through the elaboration of ROS and inflammatory cytokines including TNF or IL-1β. About the role of ROS, ablation of monocytes/macrophages significantly reduces aortic superoxide production, vascular dysfunction, and blood pressure during Ang II–induced hypertension.38 Inversely, adoptive transfer of WT, but not of NADPH oxidase-null monocytes, can restore vascular oxidative stress and hypertension.47 Complementing their intrinsic production of ROS, infiltrating monocytes in the aorta can uncouple nitric oxide (NO) synthase 3, thus amplifying vascular oxidative stress in hypertension.40About the role of macrophage cytokines, TNF augments salt appetite and promotes sodium reabsorption in the thick ascending limb of the nephron by suppressing NO synthase 3 expression.48–50 TNF deficiency, therefore, ameliorates hypertension during RAS activation.47,48 Our recent studies suggest that macrophages may similarly potentiate hypertension through their secretion of IL-1.51 Accordingly, mice lacking the receptor for IL-1α and IL-β have enhanced accumulation of NO-expressing macrophages in the kidney early in the course of hypertension and are partially protected from Ang II–induced blood pressure elevation. In our model, IL-1 receptor stimulation releases the NKCC2 sodium cotransporter from tonic inhibition by NO leading to enhanced salt retention during RAS activation. IL-1 receptor activation seems to attenuate NO secretion from intrarenal macrophages by curtailing NO synthase 2 expression. Thus, monocytes/macrophages can promote hypertension via the interlocking actions of ROS and M1 cytokines. Nevertheless, the effects of these M1 cytokines on blood pressure may depend on their absolute levels and localization as pharmacological infusions of TNF or IL-1 can promote natriuresis.49,52,53Two important recent findings further confound the simplistic notion that myeloid cells uniformly promote blood pressure elevation. First, mononuclear phagocytes in the dermis exert antihypertensive actions by allowing the mobilization and removal of nonosmotically stored sodium and by driving vasodilatory prostanoid production.54,55 Second, a unique population of Gr-1–expressing myeloid-derived suppressor cells can attenuate chronic elevations in blood pressure, at least in part by curtailing the prohypertensive effects of activated T lymphocytes in the vasculature.56 Accordingly, the actions of myeloid cell populations in hypertension depend on the inflammatory mediators they elaborate and their effects on oxidant stress in cardiovascular control centers, analogous to the actions of T-lymphocyte subsets discussed below.As monocytes and macrophages express AT1 receptors, the hypothesis that Ang II promotes hypertension, in part, by stimulating the macrophage AT1 receptor would be consistent with the pathogenic actions of AT1 receptors in the target organ. Indeed, several in vitro experiments support this possibility. For example, incubation of a human monocyte cell line with Ang II elicits activation of nuclear factor-κB signaling and promotes the release of TNF via an AT1 receptor–dependent pathway.57–59 Moreover, phagocytic capacity is reduced in rodent macrophages lacking the AT1A receptor.22 The reported effects of the AT1 receptor activation of macrophage migration have been inconsistent. Whereas the AT1 receptor inhibition attenuated CCR2-dependent migration of monocytes isolated from hypertensive rats,60 we were not able to appreciate alterations in CCL2-induced migration of macrophages from AT1A receptor–deficient mice. Collectively, the in vitro studies above would suggest that disrupting AT1A receptor signals may interfere with several important monocyte/macrophage functions. Nevertheless, approaches using pharmacological antagonists may be confounded by off-target effects, and the development or phenotype of a macrophage from a mouse that is globally deficient of the AT1A receptor may be altered by the absence of AT1A receptor signaling in other immune and even nonimmune cell lineages.To circumvent these potential confounders, we used a conditional gene targeting strategy to selectively delete the coding exon from the Agtr1a gene in LysM-expressing myeloid cells of mice (LysMCre+Agtr1aflox/flox=macro knockout). We then compared renal injury and blood pressure elevation in these animals and WT controls (LysM Cre-Agtr1aflox/flox=WT) during RAS activation.10 We found that the macro knockout animals had a chronic hypertensive response to Ang II similar to that of the WTs but had exaggerated levels of tubular and interstitial injury in the kidney. These findings were consistent with the protective actions of AT1A receptors on immune cells detected in our earlier BMT study21 but could not explain the exaggerated levels of hypertension seen in our AT1A receptor–deficient bone marrow chimeras. In particular, our conditional gene targeting approach revealed a capacity for the macrophage AT1A receptor to mitigate fibrosis in the kidney,10 confirming earlier studies from the Ichikawa group using bone marrow chimeras.22 In our hands, activating the AT1A receptor on macrophages in vitro suppressed the emergence of the proinflammatory M1 phenotype, which was reflected in vivo by attenuated expression of M1 cytokines including TNF and IL-1β in the macro knockout kidney during RAS activation,10 consistent with the findings of Ma et al23 in their model of obesity-related glomerulopathy.23 One caveat with our LysM Cre deletion strategy is that this approach may have also deleted AT1A receptors from neutrophils, and neutrophils are now receiving attention for their potential role in blood pressure regulation.61 Notwithstanding this limitation, our studies would indicate that activating the AT1 receptor directly on macrophages actually suppresses target organ damage in hypertension, particularly within the kidney, raising the possibility that the effects of global RAS activation to promote inflammation accrue from the activation of AT1 receptors in the target organ or, at least, in nonmyeloid hematopoietic cells (Figure).Download figureDownload PowerPointFigure. Interactions between the renin–angiotensin system (RAS) and immune system during the pathogenesis of hypertension. Inappropriate RAS activation increases circulating angiotensin (Ang) II. Elevated Ang II directly promotes sodium retention in the kidney and systemic vascular constriction. During hypertension, T cells and monocytes/macrophages accumulate in the kidney and vasculature where they mediate tissue injury and deleterious remodeling. Immune cells harbor the type 1 Ang II receptor, AT1A. In an apparent feedback mechanism, ligation of the AT1A receptor constrains T-cell accumulation around the renal blood vessels, and activation of the AT1A receptor on T cells and macrophages limits their differentiation toward the proinflammatory Th1 and M1 subsets, respectively. This inhibition of Th1 and M1 polarization attenuates damage to the kidney during hypertension and mitigates the emergence of renal fibrosis that culminates in organ failure.T Lymphocytes, the AT1 Receptor, and HypertensionT lymphocytes are key constituents of the adaptive immune system. As such, they are recruited by innate immune cells to aide in the specific response against pathogens. Innate immune cells present pathogen-derived antigens to T cells in peripheral lymphoid tissue. T cells express specific antigen receptors and respond to a cognate antigen by clonal expansion. After expansion, T cells travel to the site of inflammation and perform their effector functions, which vary depending on their subclassification. CD4+ T cells can release a wide range of cytokines and are often referred to as T helper (Th) cells. CD8+ T cells, on the contrary, directly kill cells by the release of cytotoxic factors. CD4+ T cells are generally divided into 4 subtypes depending on their cytokine profile: Th1, Th2, Th17, and Treg. Although additional T-helper subsets have recently been defined, such as Th9 and Th22, our understanding of their role in cardiovascular physiology is limited.62–64 Proinflammatory Th1 cells release cytokines such as interferon-γ, TNF, and IL-12 and stimulate macrophages and CD8+ T cells.65 Th2 cells stimulate B-cell antibody production by secreting the cytokines IL-4, IL-9, and IL-13. Th17 cells are proinflammatory and have been implicated in the pathogenesis of several autoimmune diseases.66 Th17 cells produce IL-17, a potent proinflammatory cytokine. Finally T regulatory cells, or Tregs, are anti-inflammatory and release cytokines that inhibit other immune cell types, including IL-10 and transforming growth factor β.67 As with myeloid cells, the distinction among different T-cell subsets in vivo is imprecise because they share many of the same surface receptors. However, each subset is driven by unique transcription factors and produce distinct cytokines that can, with some difficulty, be measured ex vivo.66,68–70T lymphocytes were experimentally linked to hypertension many years ago. However, a landmark study by Guzik et al47 in 2007 sparked a recent upsurge of studies examining the actions of T cells in hypertension. In the studies by Guzik et al,47 lymphocyte-deficient (Rag1−/−) mice had attenuated Ang II–induced hypertension, and adoptive transfer of WT T cells, but not of B cells, restored the hypertensive response. Since then, T cells have been implicated in experimental models of preeclampsia,71 pulmonary hypertension,72 salt-sensitive hypertension,73 deoxycorticosterone acetate-salt hypertension,47 and others. The mechanisms by which T cells intensify tissue injury and elevate blood pressure during hypertension are areas of intense investigation but include contributions to endothelial dysfunction in the vasculature47 and inappropriate sodium retention in the kidney,74 both of which accrue at least, in part, from local generation of ROS.75Canonical T-cell activation occurs in peripheral lymphoid tissue and requires recognition of peptide antigens on the surface of antigen-presenting cells via the T-cell receptor. Also required for T-cell activation are antigen-presenting cell costimulatory signals via receptors proximal to the T-cell receptor.76 Whereas the proportion of activated circulating CD4+ T cells increases during Ang II–induced or deoxycorticosterone acetate-salt hypertension, genetic or pharmacological inhibition of T cell costimulation blocks T-cell activation and attenuates blood pressure elevation in these models.77 With regard to the antigen(s) responsible for eliciting T-cell activation in hypertension, little is known. A novel hypothesis from Harrison et al78 suggests that intrinsic proteins within antigen-presenting cells are structurally modified via byproducts of NADPH oxidase activity during hypertension and thus are presented as antigens to T cells.78 Pharmacological prevention of this protein modification in vivo attenuated hypertension. In separate studies, Pons et al79 implicated heat-shock proteins, particularly HSP70, as a renal autoantigen in salt-sensitive hypertension. These studies would suggest that T-cell immunity in hypertension is driven by antigen presentation.Both CD4+ and CD8+ T cells infiltrate the kidney and vasculature during hypertension and contribute to tissue injury and dysfunction by a variety of putative mechanisms, including the production of ROS and the release of proinflammatory cytokines. CD8+ T cells are capable of elaborating ROS and seem to play a more critical role than CD4+ T cells in potentiating blood pressure elevation.80 ROS drive endothelial dysfunction, sodium retention, and tissue injury. The amount of ROS in T cells increases on activation,81 and adoptive transfer of NADPH oxidase-null T cells into Rag1−/− mice failed to fully restore the Ang II–induced hypertension and vascular dysfunction seen in Rag1−/− mice repopulated with WT T cells.47 Moreover, CD4+ Th1 cells elaborate TNF, a potent proinflammatory cytokine that induces ROS production, activates other immune cells,82 and potentiates sodium retention, as mentioned above. Inhibition of TNF signaling attenuates hypertension and reduces end-organ damage.47,83 Nevertheless, genetic deletion of proinflammatory Th1 cells ameliorates glomerular damage without affecting blood pressure,11 suggesting that the actions of TNF produced by nonlymphoid cells in the central nervous system and the kidney to promote salt appetite and reabsorption, respectively,48–50 may figure more prominently in the pathogenesis of hypertension than T-cell TNF. The release of IL-17 by tissue-infiltrating Th17 cells exacerbates hypertension during RAS activation.84 By contrast, repeated adoptive transfer of T regulatory cells diminishes vascular injury and Ang II–induced blood pressure elevation.85 Thus, T-cell subsets can have drastically varying effects on the hypertensive response depending on their capacities to generate ROS and their effects on the cytokine milieu in the kidney and vasculature.As with other immune cells, expression of the AT1 receptor on T cells guides their differentiation and function with surprising consequences in the setting of hypertension. In our hands, a conditional gene targeting strategy revealed protective actions of the T-cell AT1A receptor in hypertension similar to our findings with the macrophage AT1A receptor.10,11 Specifically, deleting the AT1A receptor from T cells in mice yielded exaggerated perivascular T-cell infiltration in the kidney and augmented albuminuria, recapitulating our earlier findings with the AT1A receptor–deficient bone marrow chimeras.21 Consistent with these findings, the T-cell AT1A receptor limited damage to the kidney glomerulus and renal expression of the injury marker Ngal (Lcn2) during RAS-mediated hypertension. However, in contrast to the macrophage AT1A receptor, the actions of the T-cell AT1A receptor did not influence the extent of tubular injury or interstitial fibrosis in our model. Congruent with the capacity of AT1A receptor activation on T cells to limit glomerular injury in hypertension, CD4+ T cells isolated from the kidney and spleen of the animals lacking the T-cell AT1A receptor had enhanced expression of the Th1 cytokines interferon and TNF. Additional studies revealed that activating the T-cell AT1A receptor limits Th1 differentiation of the T cell and thereby attenuates hypertensive kidney damage by suppressing the Th1 transcription factor T-bet (Figure).11,50,68Studies using T lymphocytes isolated from mice that are globally deficient of the AT1A receptor are more consistent with the view that the T-cell AT1A receptor promotes rather than suppresses inflammation. For example, splenic lymphocytes from Atgr1a−/− animals showed blunted proliferative responses after allogeneic stimulation.8 In vitro, these Agtr1a−/− T cells had impaired cytokine generation,9 and adoptive transfer of these cells into Rag1−/− mice only partly restored the hypertension and vascular dysfunction observed after adoptive transfer of WT T cells.47 One interpretation to reconcile the discrepant findings with the global versus conditional Agtr