**3. Angiotensin II and autoimmunity**

**1. Introduction**

110 Renin-Angiotensin System - Past, Present and Future

fibrogenic pathways [2].

experimental models.

**2. RAS as an inflammatory cascade**

potency of deleterious inflammatory responses [3].

The renin-angiotensin system (RAS) is a hormone system playing an important role in the pathogenesis of inflammation and autoimmune dysfunction [1]. RAS pathway elements are produced intrinsically in many diverse tissues, including the retina for controlling local inflammatory responses and maintaining local homeostasis [1]. While RAS is important for controlling normal inflammatory responses, hyperactivation of this pathway is disclosed to potentiate oxidative stress and inflammatory responses by the activation of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidases [2]. The tissue-specific RAS is believed to exert diverse physiological effects locally independent of circulating angiotensin II (AT II), which functions as the effector arm of RAS causing potent pro-inflammatory responses via angiotensin type 1 receptor (AT1R) [1]. AT II is considered to stimulate tissue factor (TF), which induces synthesis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in several cell lines including monocytes [3]. The second arm of RAS is considered to establish systemic and local protective axis against inflammation and autoimmune dysfunction via angiotensin-converting enzyme 2 (ACE2), which cleaves AT II to angiotensin-(1–7) [2]. AT (1–7) is reported to counteract the effects of AT II by negatively affecting inflammatory responses, negatively modulating leukocyte migration, cytokine expression and release, and

Uveitis is considered as an intraocular inflammatory disorder caused by infectious agents or autoimmune mechanisms [4]. The purpose of this chapter is to analyze both pro-inflammatory and protective role of RAS in ocular inflammation and uveitis both in humans and

Renin is considered to cleave angiotensinogen to AT1 that is further processed by ACE/ACE2 to different AT cleavage products including AT II, which is regarded as a principle effector molecule of the RAS [3]. The major functions of AT II are reported to be mediated by AT1R, which is considered to activate directly the key signaling pathways for cell growth and hypertrophy [4]. AT1R has been also shown to activate NF-κB and activator protein 1 (AP-1) to initiate the transcription of multiple proinflammatory genes [4]. AT II is disclosed to activate epidermal growth factor receptors (EGFR) to induce fibronectin synthesis and transforming growth factor beta (TGF-β) activity to promote fibrosis and extracellular matrix formation [3]. The effects of circulating and tissue RAS are considered to be controlled with RAS inhibitors, which prevent not only hypertension but also protect tissues against injury by limiting the

Recently, several studies have revealed that modulators of the RAS-including ACE inhibitors or AT1R antagonists display beneficial effects in the treatment of cardiovascular diseases, ath-

erosclerotic, neurodegenerative, autoimmune, and inflammatory diseases [5–8].

The modulatory effect of AT II on T-cell responses in autoimmune diseases has been disclosed by a recent study [9]. The effect of AT II in the development of Th1/Th17-mediated multiple sclerosis (MS) has been disclosed in experimental autoimmune encephalomyelitis (EAE)[10]. Elevated levels of AT II, IFN-γ, and IL-17 cytokines have been shown in the peripheral CD4<sup>+</sup> T cells from EAE mice [10]. AT1R is also considered to involve in experimental autoimmune uveitis (EAU) and experimental autoimmune myocarditis (EAM) through its effect on T-cell function [11]. A recent study has highlighted the role of AT1R in glomerular inflammation associated with autoimmune disease in mice leading to the inflammation resembling human systemic lupus erythematosus [12]. AT1R has also been disclosed in the pathogenesis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE) [13]. The expression of renin, ACE, and AT1R has been shown to be upregulated in macrophages, DCs, and T cells during the course of the MOG-EAE [13].

### **4. Angiotensin II promotes inflammation and tissue injury**

Inflammatory process is considered to involve activation of the endothelium of blood vessels and expression of diverse endothelial cell selectins that have been shown to lead the extravasation of specific leukocyte populations to the site of injury [14].

The expression and secretion of vascular endothelial growth factor (VEGF) by RAS and AT II have been disclosed to increase local vascular permeability [14]. AT II has also been disclosed to promote endothelial dysfunction through COX-2 activation, which generates vasoactive prostaglandins and reactive oxygen species (ROS) [15]. AT II is considered to favor the recruitment of infiltrating inflammatory cells into tissues by stimulating the production of specific cytokine/chemokines. AT II has been shown to induce the production of the potent monocyte chemoattractant MCP-1 in cultured monocytes [15]. Elevated levels of AT II associated with increased expression of MCP-1 and C–C chemokine receptor, CCR2, have been disclosed in the aorta of spontaneously hypertensive rats [16]. Modulation of MCP-1/CCR2 via AT1R blockade has been revealed to reduce vessel inflammation in hypertensive rats [16]. AT II-induced macrophage infiltration in the arterial wall was shown to be virtually absent in CCR2-deficient mice [16]. In models of progressive nephropathies, interstitial accumulation of macrophages was shown to be accompanied by increased renal expression of MCP-1, and renoprotection was provided by the ACE inhibitor lisinopril, which was considered to reduce MCP-1 expression and control inflammation [17]. Dendritic cells (DCs) and highly specialized antigen-presenting cells (APCs) were considered to mediate the pro-inflammatory activity of AT II [18]. Cultured DCs have been shown to express both AT II receptors and AT II, which were considered to enhance DCs migration, maturation, and antigen presenting ability [18]. Recent study in rats with subtotal renal ablation has disclosed blockade of AT II synthesis and its biological activity that resulted in reduction of local DC accumulation and attenuation of tubulointerstitial damage [19]. In another study considering cultured mesangial and vascular smooth muscle cells, AT II via AT1R signaling was shown to stimulate TLR-4 expression that was considered to promote cellular oxidative injury, apoptosis, and inflammation [20]. T cells were considered to show the pro-inflammatory effects of AT II via AT1R and endogenous RAS, which has been disclosed to modulate T-cell proliferation, cytoskeletal rearrangements, migration, and release of specific cytokines and chemokines [20].
