**6. Hypertension and age-related macular degeneration**

Even though age is the major determinant for developing AMD, clinical and epidemiolog‐ ic studies have suggested systemic vascular disease, especially hypertension, as an impor‐ tant risk factor for AMD [3,119] and a correlation between AMD and aging and hypertension [3, 120]. Aging is the risk factor with the greatest correlation with incidence, prevalence and severity of AMD, but the age-related susceptibility factors remain completely unknown [3,120]. However, increased sensitivity to the injurious effects of hypertension and to oxidantinjury are all more severe in the elderly than in the young [121-123]. For exemple, the interaction of Angiotensin II (Ang II) (the most important hormone associated with hyperten‐ sion) with AT1 receptors, produces ROS, and with advancing age, oxidative alterations accumulate in cellular components, including those in the antioxidative defense systems, due to disrupted redox regulation during aging can influence the gene transcription and signal transduction pathways.

local RAS in the retina, its exact role and its possible relationship with the systemic RAS remain poorly understood. The fact that AT1R is localized at the basolateral membrane of the RPE, which faces the blood side of the epithelium, suggests that the activity of the systemic RAS is a part of that signaling. Interestingly, it has been shown that modulation of the systemic RAS (e.g. by systemic application of ACE inhibitors) changes neuronal activity within the retina, mainly of bipolar cells and amacrine cells as monitored by electroretinography [139,141,142]. Moreover, modulators of the systemic RAS alter renin expression in the RPE [138] and plasma Ang II can not cross the intraocular space [143] suggesting that the systemic RAS most likely

Cigarette Smoking and Hypertension Two Risk Factors for Age-Related Macular Degeneration

http://dx.doi.org/10.5772/53958

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Ang II mediates its biological effects through the activation of AT1R and AT2R receptors. It is, however, through AT1R activation that Ang II elicits most of its well known effects, including vasoconstriction, electrolyte homeostasis, fibrosis, inflammation and proliferation. In the eye, AT1R activation has been implicated in the pathogenesis of many ocular disorders such as diabetic retinopathy [144,145], neovascularization in hypoxic-induced retinopathies [146-148] and age-related macular degeneration [59,60,149]. We postulate that the interaction of Ang II with AT1R, one of the most important oxidative stress inducer: a) induces blebs formation through reactive oxygen intermediate (ROS) production by activation of NADPH promoting bleb accumulation under the RPE as BLD and b) increases MMP-2 activity, MMP-14, and basigin, major mediator of ECM turnover through MAPK phosphorylation, and pro-inflam‐ matory monocyte chemoattractant protein-1 (MCP-1) production through NF-kB activation by RPE stimulating RPE basement membrane breakdown and infiltration of pro-inflammatory macrophages to sub-RPE deposit areas, where they will scavenge, release inflammatory mediators, growth factors or other substances, which may promote complications and progression to CNV [37,51,62]. Moreover, we propose that Ang II decreases TNFSF15, an antiangiogenic cytokine expressed in inflammatory diseases, altering the balance between

As mentioned previously, a substantial body of literature suggests a role for oxidant injury to the RPE as a putative mechanism in the pathogenesis of AMD and addresses the protective actions of anti-oxidant. Although intuitively obvious, oxidant injury can induce either lethal responses, leading to cell death, or nonlethal responses inducing a functional change from baseline compatible with continued life of the cell but leading to dysfunction of the tissue or organ. Most studies focus on oxidant-mediated death of RPE [150-153]. Yet, RPE death (socalled geographic atrophy) is a very late stage of dry AMD, resulting from a very chronic and progressive process. Subretinal deposits and thickening of BrM, the hallmarks of early AMD, develop decades before the RPE cells actually die. Therefore, nonlethal cellular responses to

Oxidative modifications in key cellular molecules such as DNA, carbohydrates, cellular proteins and cell membranes can often produce a cytotoxic chain reaction that contributes to

influences the intraocular RAS through the RPE.

TNFSF15 and VEGF required for normal angiogenesis.

RPE oxidant injury must contribute to early AMD.

**7. Oxidative injury to the RPE**

Hypertension is of particular interest among the systemic risk factors, due to its increasing incidence in Western societies. In several cross sectional and case control studies, systemic hypertension was associated with increased prevalence and progression of the severity and incidence of drusen [124] and with the development of wet AMD [125-127]. Interestingly, a recent study provides a strong association between hypertension and the development of wet AMD in the presence of early AMD [128]. Despite of the apparent link between AMD and hypertension, these studies make no mention of the mechanism(s) by which hyperten‐ sion may induce or contribute to the pathogenesis of dry AMD and its progression from early AMD to CNV.

Traditionally, hypertension is believed to contribute to chronic diseases by at least two distinct mechanisms: hemodynamic injury and humoral factors [129-131]. Hemodynamic injury refers to mechanical damage induced by flow turbulence in large vessels or stretch‐ ing of capillaries induced by increased blood pressure. Humoral factors refer to cellular activities induced by hormones or growth factors associated with hypertension [129,130] shuch as Ang II, which is upregulated in hypertension, present in the blood of many hypertensive patients and has been demonstrated to activate specific receptors to induce various cellular functions. Ang II as the molecular surrogate for the effects of hypertension in AMD, and its properties will be described below.

The classical view of the renin-angiotensin system (RAS) as a systemic regulator of blood pressure has been extended, and a substantial number of studies have highlighted the importance of local RAS in a variety of extra-renal tissues, including adrenal glands [132], thymus [133] and recently in the eye [134,135]. In the eye, Ang II, and Ang II type 1 and type 2 receptors (AT1R, AT2R) have been found in the retina, particularly in the retinal pigment epithelium (RPE) [59,60,136-139]. Similarly, studies in rat retinal tissues also suggested local synthesis of both renin and angiotensin convertingenzyme (ACE) [140]. Along this line, Milenkovic et al. (2010) demonstrated that the RPE expresses renin and secretes it towards the retinal side. The presence of the most important RAS components in the retina implies a physiological function of RAS within the eye. However, despite the considerable evidence for local RAS in the retina, its exact role and its possible relationship with the systemic RAS remain poorly understood. The fact that AT1R is localized at the basolateral membrane of the RPE, which faces the blood side of the epithelium, suggests that the activity of the systemic RAS is a part of that signaling. Interestingly, it has been shown that modulation of the systemic RAS (e.g. by systemic application of ACE inhibitors) changes neuronal activity within the retina, mainly of bipolar cells and amacrine cells as monitored by electroretinography [139,141,142]. Moreover, modulators of the systemic RAS alter renin expression in the RPE [138] and plasma Ang II can not cross the intraocular space [143] suggesting that the systemic RAS most likely influences the intraocular RAS through the RPE.

Ang II mediates its biological effects through the activation of AT1R and AT2R receptors. It is, however, through AT1R activation that Ang II elicits most of its well known effects, including vasoconstriction, electrolyte homeostasis, fibrosis, inflammation and proliferation. In the eye, AT1R activation has been implicated in the pathogenesis of many ocular disorders such as diabetic retinopathy [144,145], neovascularization in hypoxic-induced retinopathies [146-148] and age-related macular degeneration [59,60,149]. We postulate that the interaction of Ang II with AT1R, one of the most important oxidative stress inducer: a) induces blebs formation through reactive oxygen intermediate (ROS) production by activation of NADPH promoting bleb accumulation under the RPE as BLD and b) increases MMP-2 activity, MMP-14, and basigin, major mediator of ECM turnover through MAPK phosphorylation, and pro-inflam‐ matory monocyte chemoattractant protein-1 (MCP-1) production through NF-kB activation by RPE stimulating RPE basement membrane breakdown and infiltration of pro-inflammatory macrophages to sub-RPE deposit areas, where they will scavenge, release inflammatory mediators, growth factors or other substances, which may promote complications and progression to CNV [37,51,62]. Moreover, we propose that Ang II decreases TNFSF15, an antiangiogenic cytokine expressed in inflammatory diseases, altering the balance between TNFSF15 and VEGF required for normal angiogenesis.
