Lymphocyte responses exacerbate angiotensin II-dependent hypertension

Abstract

cyte responses exacerbate angiotensin II-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 298: R1089-R1097, 2010. First published February 10, 2010 doi:10.1152/ajpregu.00373.2009.-Activation of the immune system by ANG II contributes to the pathogenesis of hypertension, and pharmacological suppression of lymphocyte responses can ameliorate hypertensive end-organ damage. Therefore, to examine the mechanisms through which lymphocytes mediate blood pressure elevation, we studied ANG II-dependent hypertension in scid mice lacking lymphocyte responses and wild-type controls. Scid mice had a blunted hypertensive response to chronic ANG II infusion and accordingly developed less cardiac hypertrophy. Moreover, lymphocyte deficiency led to significant reductions in heart and kidney injury following 4 wk of angiotensin. The muted hypertensive response in the scid mice was associated with increased sodium excretion, urine volumes, and weight loss beginning on day 5 of angiotensin infusion. To explore the mechanisms underlying alterations in blood pressure and renal sodium handling, we measured gene expression for vasoactive mediators in the kidney after 4 wk of ANG II administration. Scid mice and controls had similar renal expression for interferon-␥, interleukin-1␤, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-␣, endothelial nitric oxide synthase (eNOS), and cyclooxygenase-2 (COX-2) in the kidney. In turn, this enhanced eNOS and COX-2 expression in the scid kidneys was associated with exaggerated renal generation of nitric oxide, prostaglandin E2, and prostacyclin, all of which promote natriuresis. Thus, the absence of lymphocyte activity protects from hypertension by allowing blood pressure-induced sodium excretion, possibly via stimulation of eNOSand COX-2-dependent pathways.inflammation; kidney diseases; T lymphocytes THE RENIN-ANGIOTENSIN SYSTEM (RAS) is a critical regulator of blood pressure and fluid homeostasis. The principal effector molecule of this system, angiotensin II (ANG II) raises blood pressure primarily through activation of type 1 angiotensin (AT 1 ) receptors (11). The important role of AT 1 receptors in the pathogenesis of hypertension is illustrated by clinical trials that show the impressive efficacy of AT 1 receptor blockers (ARBs) in ameliorating hypertension and its complications, including chronic kidney disease (CKD) and cardiac hypertrophy (3, 13, 37).In these trials, RAS inhibition appears to protect from end-organ damage to a greater degree than can be explained solely by blood pressure reduction (3, 63). Blockade of proinflammatory cellular effects of ANG II represents one blood pressure-independent mechanism through which ARB therapy could protect against target organ injury. For example, ANG II stimulates NF-B activation and interferon-␥ expression in the kidney, and immunosuppression can reverse these effects (8,45,46). Moreover, ANG II can drive lymphocyte proliferation (48), a...

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

“…It was Guzik et al who observed that mice lacking T cells are resistant to the development of both Ang II and deoxycorticosterone acetate-salt induced hypertension, and adoptive transfer of T cells, but not B cells, restored hypertension in these mice. 3 Despite this investigation and others 29,30 considerably improving our understanding of the adaptive immune system in the pathogenesis of hypertension and vascular dysfunction, there are still gaps in knowledge surrounding how it is signaled for involvement in the first place.…”

“…3,29,30 T cells also have a central role in the development of autoimmune disorders, and as a result, loss of immunological tolerance has been proposed as an underlying factor in hypertension. 36 Interestingly, CQ and other antimalarial agents have long been used as therapeutic agents in the treatment of autoimmune conditions (e.g., rheumatoid arthritis and systemic lupus erythematosus 37,38 ), even though their precise mechanism(s) of action are still not known.…”

Immune Mechanisms in Arterial Hypertension

“…These results have been confirmed in severe combined immunodeficiency mice and in Dahl salt-sensitive rats in which the RAG-1 or the essential T cell receptor component CD3 have been deleted using zinc finger nuclease technology. [4][5][6] This seminal work has caused great interest in the immunologic aspects of hypertensive disease. [7][8][9][10] This review will give a brief overview of the components of the innate and adaptive arm of the immune system in hypertension and summarize recent advances in immunologic research, with a special focus on their potential relevance for hypertension and hypertensive endorgan damage.…”

In Search of the T Cell Involved in Hypertension and Target Organ Damage

“…1,2 More recently, we have shown that RAG1 −/− mice, which lack mature T and B lymphocytes, are protected from severe angiotensin II-induced or deoxycorticosterone acetatesalt hypertension and vascular damage. 4 Similar findings were confirmed in mice with severe combined immunodeficiency, 5 and more recently in RAG1 −/− Dahl salt-sensitive rats, which were protected from salt-sensitive hypertension, heart hypertrophy, and renal damage. 6 These hypertensive phenotypes are dependent on T-cell activation.…”