**10. Conclusions**

(Fig. 16C). In preliminary experiments, we have also demonstrated that mice receiving subconjunctival injections of hydroquinone exhibeted a rudimentary form of BLD, often demonstrating small vesicular vesicles bleblike structures (Reinoso, et al. IOVS 2005;46:ARVO E-Abstract 3010). In addition, RPE from mice exposed to hydroquinone in drinking water showed increased levels of phosphorylated Hsp25, p38 and ERK [205], suggesting that phosphorylated Hsp25 might be a key mediator in early cellular events associated with actin

**Figure 16.** Transmission electron microscopy of the outer retina and choroid from a 16-month-old female mouse fed with a regular fat diet for 4 months. (A) Outer retina and choroid of a mouse fed a regular diet without oxidant showed a normal RPE, BrM, and choriocapillaris. (B) Outer retina and choroid of a mouse fed a regular diet and ex‐ posed to HQ (0.8% for 4 months) in drinking water revealed sub-RPE deposits characterized by accumulation of mod‐ erately severe BLD with dense granular material between the RPE and its basement membrane (\*), compatible with a high mean severity score. The specimen, also, shows the abnormal choriocapillaris endothelium with increased thick‐ ening and loss of fenestration. (C) TEM of the outer retina and choroids from another 16-month-old female mouse fed a regular diet and exposed to HQ. The specimen shows moderately thick BLD with bandes structures (\*) and occasion‐

We used Ang II to determine whether hypertension-associated Ang II was important for ECM regulation in RPE and the development of sub-RPE deposits. We reported that Ang II-treated mice had increased blood pressure as well as plasma and ocular levels of Ang II relative to control mice [60]. Ang II also regulated AT1a and AT1b receptor mRNA expression, and the intracellular concentration of calcium [Ca2+]I, showing that Ang II AT1 receptor is functional. In addition, MMP-2 activity, and type IV collagen accumulation were regulated by Ang II. Concurrent administration of Ang II with the AT1 receptor blocker prevented the increase in blood pressure and rise in ocular Ang II levels, as well as the calcium and MMP-2 responses. In contrast, the type IV collagen response to Ang II was prevented by blockade of AT2 receptors, but not AT1 receptors. Plasma Ang II levels were not modified by the AT1 or AT2 receptor blockade. In addition, Ang II stimulates MMP-14, basigin, and phosphorylation of ERK, p38, and JNK in RPE sheets from mice. These effects were mediated by Ang II type 1

al blebs (black arrows). CC, choriocapillaris, Magnification: (A, C) x25,000; (B) x7,200.

receptors [344].

reorganization and bleb formation involved in sub-RPE deposits formation.

72 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

In summary, we postulate that cigarette smoke-related and Ang II play a role in the develop‐ ment of dry AMD and its progression to wet AMD. Although our hypothesis remains to be proven, we have proposed new ideas and suggested different mechanisms highlighting Hsp27, MMP-2, basigin, MMP-14, MCP-1, MAPK, and TNFSF15 as potential disease-related proteins as well as biochemical pathways for potential therapeutic strategies, which might result in prevention of more severe and irreversible late stages of this dreadful disease. Our goal is to intervene promptly in the early stages of the disease so that progression to the more severe late forms of AMD can be prevented. In this respect, RPE-derived MMPs and blebs formation are potential target due to their pivotal role in stimulating drusen formation and progression into CNV. Levels of phosphorylated Hsp27, glycosilated basigin and MMP-14, as well as, MCP-1 and TNFSF15 could be markers, which may contribute and aid to the ophthal‐ mologic community in the management of the drusen. Moreover, AT1 receptor antagonists and p38/ERK1/2 MAPK blockers could be used successfully on the prevention of sub-RPE deposits formation in selected high-risk AMD patients.
