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M.E. Marin Castaño; Angiotensin II Receptor Expression and Function in Retinal Pigment Epithelium. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1811.
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Purpose: The pathogenesis of age–related macular degeneration is multifactorial, and hypertension (HTN) has been implicated. We postulate that hypertension might contribute to RPE injury and subretinal deposit formation through the actions of hypertension–associated hormones like angiotensin II (Ang–II). Ang–II, through interactions with its two cell surface receptors, can regulate the synthesis of molecules important in the maintenance of the extracellular matrix, especially MMP–2 and MMP–9. Previously, we have demonstrated that human RPE express both Ang–II receptors. In this study, we confirm that murine RPE also express both angiotensin receptors, and characterize the regulation of RPE expression of MMP–2 and MMP–9 by Ang–II. Methods: Western blot and RT–PCR were used to characterize angiotensin receptor expression in murine and human RPE. Confluent cultures of human ARPE–19 cell line in low serum conditions were incubated with or without physiologic concentrations of Ang–II (10–11 to 10–7 M), for different times. In parallel experiments, APRE–19 cells were incubated with a specific AT1 or AT2 receptor antagonist. Supernatants were collected to assess MMP–9 and MMP–2 activity. Results: We confirm that both human and mouse RPE express all the typical angiotension II receptor subtypes. Time course analysis demonstrated that Ang–II demonstrated two peaks of upregulated MMP–9 and MMP–2 activity, one at 3 to 6 hours after exposure and a second peak at 48 hours post exposure. Both Candesartan (AT1 antagonist) and PD123319 (AT2 receptor antagonist) partially attenuated the Ang–II associated MMPs activity, and both together abolished the effect. Conclusion: This study confirms the presence of Ang–II receptors in both human and murine RPE cells. Ang–II increases expression of MMP–2 and MMP–9 activity in physiological concentrations. These data support the hypothesis that Ang–II may regulate extracellular matrix molecule expression in hypertensive patients who have age–related macular degeneration.
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