Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II

Abstract

Striker GE, Praddaude F, Alcazar O, Cousins SW, MarinCastañ o ME. Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II. Am J Physiol Cell Physiol 295: C1633-C1646, 2008. First published October 15, 2008 doi:10.1152/ajpcell.00092.2008.-The early stage of age-related macular degeneration (AMD) is characterized by the formation of subretinal pigment epithelium (RPE) deposits as a result of the dysregulation in the turnover of extracellular matrix (ECM) molecules. However, the mechanism involved remains unclear. Hypertension (HTN) is an important risk factor for AMD, and angiotensin II (ANG II) is the most important hormone associated with HTN. However, the relevance of ANG II receptors and ANG II effects on RPE have not been investigated yet. Therefore, the expression and regulation of ANG II receptors as well as the ECM turnover were studied in human RPE. ANG II receptors were expressed and upregulated by ANG II in human RPE. This regulation resulted in functional receptor expression, since an increase in intracellular concentration of calcium was observed upon ANG II stimulation. ANG II also increased matrix metalloproteinase (MMP)-2 activity and MMP-14 at the mRNA and protein levels as well as type IV collagen degradation. These ANG II effects were abolished in the presence of the ANG II receptor subtype 1 (AT1) receptor antagonist candesartan. In contrast, ANG II decreased type IV collagen via both AT1 and AT2 receptors, suggesting a synergistic effect of the two receptor subtypes. In conclusion, we have confirmed the presence of ANG II receptors in human RPE and their regulation by ANG II as well as the regulation of ECM molecules via ANG II receptors. Our data support the hypothesis that ANG II may exert biological function in RPE through ANG II receptors and that ANG II may cause dysregulation of molecules that play a major role in the turnover of ECM in RPE basement membrane and Bruch's membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD. calcium; hypertension; Bruch's membrane EARLY AGE-RELATED MACULAR DEGENERATION (AMD) is one of the most common irreversible causes of severe loss of vision in elderly population (23,39). Dysfunction of retinal photoreceptors is the ultimate cause of vision loss. However, the initial pathogenic target of AMD is the retinal pigment epithelium (RPE) and the subjacent extracellular matrix (Bruch's membrane, or BrM) (25). Although age is the major determinant for developing AMD, clinical studies have revealed a number of systemic and environmental risk factors (23,49,54). Among them, hypertension (HTN) is of special relevance (29,34,37,39). However, the mechanism(s) by which HTN may affect AMD remains unclear. Interestingly, different reports have related that angiotensin II (ANG II), the final product of the renin-angiotensin system (RAS) and the most important hormone associated with HTN, may contribute to chronic diseases (17,43,58,69).Expression and localization ...

Angiotensin II–Induced MMP-2 Activity and MMP-14 and Basigin Protein Expression Are Mediated via the Angiotensin II Receptor Type 1–Mitogen-Activated Protein Kinase 1 Pathway in Retinal Pigment Epithelium

“…1,18,23,26 In this regard, MMP-2 is the most abundant and important MMP enzyme synthesized by the RPE relevant to retinal disorders such as AMD, in which its activity is dysregulated. 53,54 Moreover, MMP-2 is crucial in degradation of ECM proteins in the RPE basement membrane and BrM 4,19,55, .…”

“…[27][28][29][30] It has been recently demonstrated that Ang II induces AT1-mediated breakdown of the RPE basement membrane by increasing MMP-2 activity in RPE. 18,26 A concomitant increase in MMP-14 expression has also been demonstrated, which might account, at least in part, for the Ang II-induced increase in MMP-2 activity. 18 Another potential regulator of MMPs is basigin (BSG), also known as extracellular MMP inducer or CD147, which is a protein that induces MMP-2 and MMP-14 in various cell types.…”

“…18,26 A concomitant increase in MMP-14 expression has also been demonstrated, which might account, at least in part, for the Ang II-induced increase in MMP-2 activity. 18 Another potential regulator of MMPs is basigin (BSG), also known as extracellular MMP inducer or CD147, which is a protein that induces MMP-2 and MMP-14 in various cell types. [31][32][33][34] BSG is expressed in human RPE and ARPE-19 cells, 35 although its function in the retina and regulation by Ang II in the RPE remain unknown.…”

“…has been demonstrated in the retina and the RPE [15][16][17][18] , which provides the molecular basis for a biological function of Ang II in the eye.…”

“…In this regard, matrix metalloproteinase (MMP)Ϫ2, the most abundant and important MMP enzyme synthesized by the RPE, is crucial for degradation of ECM proteins in the RPE basement membrane and BrM. 18,[22][23][24][25][26] It has been well established that action of Ang II regulates expression of ECM proteins in various tissues. [27][28][29][30] It has been recently demonstrated that Ang II induces AT1-mediated breakdown of the RPE basement membrane by increasing MMP-2 activity in RPE.…”