**The Role of Renin-Angiotensin System in Ocular Inflammation and Uveitis**

Ozlem Sahin and Alireza Ziaei

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69509

### **Abstract**

The renin-angiotensin system (RAS) plays an important role in the pathogenesis of inflammation and autoimmune dysfunction. Uveitis is a sight-threatening intraocular inflammatory disorder caused by infectious agents, autoimmune mechanisms, exposure to toxins and many other unknown factors. Most components of RAS have been identified in every organ including the eye. 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 proinflammatory responses via Angiotensin type 1 receptor (AT1R). AT II mediated stimulation of tissue factor (TF), the principal initiator of the clotting cascade and a major regulator of haemostasis and thrombosis rapidly inducible by inflammatory agents in several cell lines including monocytes. Activation of NFκB, a key redox-sensitive transcription factor encoding for the TF gene, plays a key role in that mechanism amplified by locally synthesized angiotensin I. (AT I) The second arm of RAS establishes systemic and local protective axis against inflammation and autoimmune dysfunction via angiotensin-converting enzyme 2 (ACE2) which is a zinc-metallopeptidase able to cleave AT II to form angiotensin-(1–7) [AT-(1–7)]. AT-(1–7), a biologically active peptide, binds to a G-protein coupled receptor Mas, and activates signaling pathways that counteract the effects of AT II by negatively effecting inflammatory responses and negatively modulating leukocyte migration, cytokine expression and release, and fibrogenic pathways. 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 experimental models.

**Keywords:** uveitis, renin, angiotensin, angiotensin converting enzyme, tissue factor

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

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 fibrogenic pathways [2].

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 experimental models.

### **2. RAS as an inflammatory cascade**

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 potency of deleterious inflammatory responses [3].

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