Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II.
Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II.
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DOI：
10.1152/ajpcell.00092.2008
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发表时间：
2008-12
期刊：
影响因子：
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通讯作者：
G. Striker;F. Praddaude;O. Alcázar;S. Cousins;M. Marin-Castaño
中科院分区：
文献类型：
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作者：
G. Striker;F. Praddaude;O. Alcázar;S. Cousins;M. Marin-Castaño
年龄相关性黄斑变性（AMD）的早期特征是由于细胞外基质（ECM）分子周转失调而形成视网膜下色素上皮（RPE）沉积物。然而，其中的机制尚不清楚。高血压（HTN）是AMD的重要危险因素，而血管紧张素II （ANG II）是与HTN相关的最重要激素。然而，ANG II受体的相关性和ANG II对RPE的影响尚未得到研究。因此，我们研究了人类RPE中ANG II受体的表达和调控以及ECM的转换。ANG II受体在人RPE中表达和上调。这种调节导致功能性受体的表达，因为在ANG II刺激下观察到细胞内钙浓度的增加。ANG II在mRNA和蛋白水平上也增加基质金属蛋白酶(MMP)-2和MMP-14的活性，以及IV型胶原的降解。这些ANG II效应在ANG II受体亚型1 （AT1）受体拮抗剂坎地沙坦存在时被消除。相比之下，ANG II通过AT1和AT2受体降低IV型胶原，提示两种受体亚型的协同作用。综上所述，我们证实了人类RPE中存在ANG II受体，并通过ANG II受体对其进行调控，同时也证实了ANG II受体对ECM分子的调控。我们的数据支持ANG II可能通过ANG II受体在RPE中发挥生物学功能的假设，并且ANG II可能导致在RPE基底膜和Bruch膜中ECM周转中起主要作用的分子失调，这提示了HTN与AMD之间联系的致病机制。
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.