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Maria E. Marin Castano, Marianne Pons; Angiotensin II-induces Extracellular Marix Metalloproteinase Inducer (basigin) Protein Expression Through AT1 Receptors Activation In Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4427.
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Accumulation of extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE) has been previously observed in eyes with age-related macular degeneration (AMD) and may play a role in the pathogenesis of AMD. Progression of the sub-RPE deposits requires degradation of ECM proteins, which are critical components of RPE basement membrane (BM) and adjacent Bruch’s membrane. In this regard, matrix metalloproteinase 2 (MMP-2) and its activator basigin may be crucial in ECM degradation and remodeling. Clinical studies have revealed hypertension (HTN) as a systemic risk factor for AMD and Angiotensin II (Ang II) as the most important hormone associated with HTN. Our laboratory has previously shown that Ang II increases MMP-2 activity in RPE in vitro and in vivo. Our goal is to explore the regulation of basigin by Ang II, which might account, at least in part, for the Ang II-induced increase in MMP-2 activity.
ARPE-19 cells were cultured to confluence and the medium was first deprived of phenol red and then serum reduced. Cells were stimulated with; a) Ang II (10-11 to 10-7 M) for 24 hours or b) with 10-7 M Ang II alone or in combination with 10-6 M candesartan, an Ang II type 1 (AT1) receptor blocker, PD123319 (10-6 M), an Ang II type 2 (AT2) receptor blocker, and/or a combination of both for 1 h before Ang II (10-7 M) exposure. Cells were then collected for protein determination. In parallel experiments C57BL/6 mice were infused via osmotic minipumps for 4 weeks with; a) saline, b) Ang II in saline, c) Ang II in combination with candesartan in drinking water, and d) Ang II in combination with PD123319 in drinking water. Systolic blood pressure was recorded using the tail-cuff plethysmography method. Animals were sacrificed for recovery of RPE sheets. Western blot analysis was performed.
Ang II stimulates basigin protein expression in both ARPE-19 cells and RPE from aging hypertensive C57BL/6 mice via AT1 receptor.
Our study suggests that activation of basigin expression by Ang II may be necessary for Ang II-induced increase in MMP-2 activity in the RPE. In addition, AT1 receptor may be an important mediator of RPE response to Ang II-induced ECM dysregulation and breakdown of the RPE BM providing helpful insight into sub-RPE deposits progression relevant to the pathogenesis of AMD.
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