Human T and Natural Killer Cells Possess a Functional Renin-Angiotensin System

Abstract

The renin-angiotensin system (RAS) plays an important role in the regulation of inflammation and in the progression of chronic kidney disease. Accumulation of inflammatory cells into the renal parenchyma has been a hallmark of chronic kidney disease; however, little is known concerning the presence and the function of RAS elements in T and natural killer (NK) cells. Here is reported a co-stimulatory effect of angiotensin II (AngII) by showing an augmentation of mitogen and anti-CD3-stimulated T and NK cell proliferation with AngII treatment. Angiotensinogen and AngI also generated the same effect, suggesting that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they express renin, the renin receptor, angiotensinogen, and angiotensin-converting enzyme by mRNA analysis. Flow cytometric analysis and Western blot revealed angiotensin receptor 2 (AT 2 ) expression in T and NK cells, whereas AT 1 expression was found in T and NK cells and monocytes by Western blot. These receptors were shown to be functional in calcium signaling, chemotaxis, and proliferation. However, AT 1 and AT 2 antagonists alone or in combination were unable to abrogate completely the effects of AngII, suggesting that another AngII receptor may also be functional in leukocytes. This is the first study to show that T and NK cells are fully equipped with RAS elements and are potentially capable of producing and delivering AngII to sites of inflammation. Because their chemotaxis is enhanced by AngII, this creates a potential inflammatory amplification system. B ecause of its hemodynamic effects, angiotensin II (AngII) plays a central role in the progression of chronic kidney diseases (CKD) and ischemic heart disease (1,2). AngII has been shown to be a potent proinflammatory molecule, and the beneficial effects of renin-angiotensin system (RAS) blockade are due not only to lowering BP but also to a reduction in inflammation (3). One of the main features of CKD is the accumulation of inflammatory cells, which plays a crucial role in disease progression (4), and recruitment of macrophages to the kidney through AngII infusion has been reported in various rodent models (5,6). In both diabetic nephropathy and atherosclerosis, monocytes/macrophages have been reported to play a key role (7-9). Monocytes have also been the primary focus of studies that have examined the interaction of AngII and inflammatory cells (10). However, the importance of T, natural killer (NK), and dendritic cells (DC) in inflammation and vascular disease has only recently begun to be appreciated. DC have been shown to present oxidized LDL to T cells, generating autoreactive T cells and promoting arterial injury (11). NK cells participate through the production of proatherogenic cytokines such as IFN-␥ (12). Previous studies on AngII-induced inflammation and its role in kidney disease primarily focused on the induction of inflammatory molecules and the paracrine effects of AngII in vascular remodeling and tissue fibrosis (13,14). Despite these ...

Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

“…[20][21][22] We hypothesized this mobile RAS might be responsible for the effect of captopril on neutrophil hypersegmentation. To identify RAS components in human neutrophils, the presence of ACE in human neutrophils was examined by reverse transcription polymerase chain reaction (RT-PCR).…”

“…Human T cell and natural killer (NK) cells display functional RAS and deliver Ang II to sites of inflammation. 20 Alveolar macrophages express ACE and produce Ang II in human atherosclerotic plaques. 21 Circulating rat leukocytes are also reported to secrete angiotensinogen, 22 and human mononuclear leukocytes possess functional components of RAS that can generate Ang II locally.…”

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

“…Recently, a number of studies have demonstrated that RAS activation could play an important role in immunologically induced inflammation (14)(15)(16). In vitro and in vivo studies have shown that Ang II could induce DCs maturation (14,17).…”

“…In vitro and in vivo studies have shown that Ang II could induce DCs maturation (14,17). Additionally, several lines of evidence demonstrate that Ang II induces Th1 and Th17 immune responses and ultimately enhances inflammation in several Ang II-mediated inflammatory diseases (15)(16)(17)(18). However, the direct regulatory effect of losartan on the function of lung DCs and Th cells in ALI remains to be fully elucidated.…”

Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

“…Accumulating experimental evidence from AT2R knockout mice or from rats under AT2R agonists further indicates that AT2R, which may be exposed to enhanced Ang II level after AT1R blockade, afford protection against MI-induced cardiac injury (5,10). Given the recent observations showing that angiotensin AT2R is abundantly expressed in immunocompetent cells and involved in cell-mediated inflammatory injury (11), it appears likely that AT2R exerts its actions through interfering with cellular inflammatory processes in the heart.…”