NDT Advance Access originally published online on December 13, 2007
Nephrology Dialysis Transplantation 2008 23(4):1107-1108; doi:10.1093/ndt/gfm867
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T-cells in angiotensin-II-induced vascular damage*
Division of Nephrology, Department of Internal Medicine, Johann Wolfgang Goethe-University Frankfurt/Main, Theodor-Stern Kai 7, 60590 Frankfurt, Germany
Helmut Geiger, Division of Nephrology, Department of Internal Medicine, Johann Wolfgang Goethe-University Frankfurt/Main, Theodor-Stern Kai 7, 60590 Frankfurt, Germany. E-mail: h.geiger{at}em.uni-frankfurt.de
Keywords: hypertension; T-cells
In this study, Guzik et al. proved that mice lacking T- and B-cells do not develop hypertension and associated vascular dysfunction in two different models of hypertension, either with high angiotensin II (angiotensin II infusion) or with low angiotensin II (DOCA salt). Transfusion of T, but not B, cells restored these abnormalities, leading to the conclusion that T-cells play an important role in the genesis of hypertension. To gain an insight into how T-cells may be involved in the mechanisms that finally cause hypertension, they examined the effects of angiotensin II on vascular infiltration of these cells. Angiotensin II markedly increased the number of T-cells in aortic periadventitial fat and stimulated vascular expression of the chemokine receptor 5 ligand RANTES. The infiltrated T-cells showed high levels of CCR5 and were negative for CD4 and CD8. Angiotensin II infusion increased T-cell expression of three specific NADPH oxidase subunits, raising the ability of T-cells to produce O2– and inducing the production of TNF
and IFN
. Adoptive transfer of T-cells lacking the angiotensin type 1 receptor or a functional NADPH oxidase resulted in blunted angiotensin-II-dependent hypertension. Treatment with the soluble TNF receptor etanercept prevented hypertension and reduced the increase in vascular O2– by angiotensin II, whereas the anti-IFN antibody had no effect.
What do cells of the immune system have to do with blood pressure? In several studies, it was shown that end organ damage of hypertension, especially in the kidney, is associated with activation of the renin–angiotensin system and infiltration of T-cells in the renal cortical interstitium. Treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker significantly reduces the number of infiltrating T-cells [1]. In the two-kidney, one-clip renovascular hypertensive rat, intercellular adhesion molecule-1 (ICAM-1) and its counterpart lymphocyte-function-associated antigen-1 (LFA-1) are involved in the recruitment of lymphocytes [2]. Angiotensin II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGR) and immunosuppressive treatment protects against angiotensin-II-induced renal damage [3]. Moreover, suppression of the adaptive immune system prevents renal damage and dysfunction in salt-sensitive hypertension [4].
Hypertension is multifactorial in origin and regulation of blood pressure involves the vasculature, the kidney, the adrenals and the central nervous system. It has been shown in experimental models that affecting the immune system by pharmacological interventions [5] or by thymectomy [6] prevents hypertension. Additionally, clinical observations point to a link between T-cells and hypertension; infusion of T-cells for treatment of cancer increases blood pressure in humans [7] and mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis [8]. On the other hand, I would stress that the hypothesis of a connection of hypertension with immune cell mechanisms has been the subject of controversy, especially because in the clinical workaday routine, hypertension is rarely reduced by immunosuppression.
The discussion of Guzik et al. focuses on the link of angiotensin II to T-cells. T-lymphocytes contain a functional NADPH oxidase and an AT1 receptor, and angiotensin II induces T-cell proliferation. Thus, many of the vascular consequences of angiotensin II were prevented in mice lacking lymphocytes. In their study, they demonstrate that the T-lymphocyte, particularly the AT1 receptor and the NADPH oxidase in T-cells, is required for the full development of hypertension. In angiotensin-II-infused mice, blockade of TNF normalizes blood pressure and vascular superoxide. Investigating the DOCA-salt model, Guzik et al. were able to show that lymphocytes may also play a role in hypertension with suppressed plasma renin and angiotensin II levels. This is of great interest because angiotensin-II-induced hypertension is mainly mediated by vasoconstriction, whereas the DOCA-salt model is completely independent of vascular tone [9,10]. Given these preconditions, Guzik provides us with some explanations as to how adoptive transfer of T-cells may induce hypertension by angiotensin II and stimulation of reactive oxygen species production via NADPH. But his study does not explain how T-cells cause hypertension under the low angiotensin II condition. A more plausible explanation is that T-cells do not modulate haemodynamics in the absence of a pathological stimulus, but they indirectly affect vascular tone or renal mechanisms independent of plasma concentration of angiotensin II.
In this context, the conclusion drawn by Guzik et al. that T-cells likely play a central role in modulation of hypertension and provide a new therapeutic target for treatment of this common disease is inconclusive. What they have shown in their experimental study is that T-cells may be involved in the early cascade of events that lead to vascular dysfunction and hypertension. Immune mechanisms including inflammation may have a place in the pathogenesis of hypertension. The association between inflammation and hypertension also recalls a similar association between low-grade inflammation and other components of the metabolic syndrome, and endothelial dysfunction, as well as increased serum levels of C-reactive protein in patients with hypertension [11,12]. A key question is whether there exists an early stage in the development of human hypertension at which we can inhibit high blood pressure by a specific intervention. A consequence of this study would be to develop preventive strategies to stop vascular dysfunction and consecutive hypertension, by T-cell-modulating therapies. As yet, we do not know when, by what means and how long T-cells should be affected or modified, and interference with the immune system may induce acute and long-term side effects. Further interventional studies are required to test the hypothesis that an early T-cell-directed therapy may affect the development of hypertension in humans.
Today we know a prisma of multiple facets that are involved in the genesis of hypertension; T-cells may be added to this list.
Conflict of interest statement. None declared.
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* Commment on Guzik TJ, Hoch NE, Brown KA et al. Role of the T cell in the genesis of angiotensin II-induced hypertension and vascular dysfunction. J Exp Med 2007; 204: 2449–2460.
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[Abstract/Free Full Text]
Accepted in revised form: 14.11.07
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