Angiotensin II-induced hypertension regulates AT1 receptor subtypes and extracellular matrix turnover in mouse retinal pigment epithelium.
Angiotensin II-induced hypertension regulates AT1 receptor subtypes and extracellular matrix turnover in mouse retinal pigment epithelium.
复制标题
DOI：
10.1016/j.exer.2009.02.020
复制
发表时间：
2009-06-15
影响因子：
3.4
通讯作者：
Marin-Castano, Maria E.
中科院分区：
文献类型：
--
作者：
Praddaude, Francoise;Cousins, Scott W.;Pecher, Christiane;Marin-Castano, Maria E.
关键词：
视网膜色素上皮（RPE）下的特定沉积物和细胞外分子的积累先前已经在患有年龄相关性黄斑变性（AMD）的眼睛中观察到，并且可能在AMD的发病机制中起作用。尽管年龄是发展AMD的主要决定因素，但临床研究显示高血压（HTN）是另一个全身性风险因素。血管紧张素II（Angiotensin II，Ang II）被认为是与HTN相关的最重要的激素。为了评估血管紧张素II与AMD的关系，我们研究了小鼠RPE是否表达功能性血管紧张素II受体亚型，以及HTN诱导的血管紧张素II是否调节这些受体的表达以及参与RPE ECM周转的关键ECM分子（MMP-2和IV型胶原）。我们使用9个月大的C57 BL/6雄性小鼠，单独或与AT 1受体拮抗剂坎地沙坦或AT 2受体拮抗剂PD 123319联合输注Ang II 4周，以确定HTN相关的Ang II是否对RPE的ECM调节重要。我们发现，小鼠视网膜色素上皮细胞表达的Ang Ⅱ受体亚型在mRNA和蛋白质水平。血管紧张素II诱导HTN和血浆和眼血管紧张素II水平升高。血管紧张素Ⅱ还调节AT 1a和AT 1b受体mRNA的表达，细胞内钙离子浓度，MMP-2活性和IV型胶原的积累。血管紧张素II与AT 1受体阻滞剂同时给药可防止血压升高和眼部血管紧张素II水平升高，以及钙和MMP-2反应。与此相反，IV型胶原蛋白对血管紧张素II的反应是通过阻断AT 2受体而不是AT 1受体来阻止的。AT 1或AT 2受体阻断剂未改变血浆Ang II水平。由于Ang II对MMP-2和IV型胶原的作用需要抑制两种Ang II受体亚型，因此这些受体可能作为潜在的治疗靶点发挥作用，以防止RPE基底膜中的ECM周转失调，这表明了解释HTN和AMD之间联系的致病机制。
Accumulation of specific deposits and extracellular molecules under the retinal pigment epithelium (RPE) have been previously observed in eyes with age-related macular degeneration (AMD) and may play a role in the pathogenesis of AMD. Even though age is the major determinant for developing AMD, clinical studies have revealed hypertension (HTN) as another systemic risk factor. Angiotensin II (Ang II) is considered the most important hormone associated with HTN. To evaluate the relationship of Ang II to AMD, we studied whether mouse RPE expresses functional Ang II receptor subtypes and whether HTN-induced Ang II regulates expression of these receptors as well as critical ECM molecules (MMP-2 and type IV collagen) involved in ECM turnover in RPE. We used 9 month-old C57BL/6 male mice infused with Ang II alone or Ang II in combination with the AT1 receptor antagonist candesartan or the AT2 receptor antagonist PD123319 for 4 weeks to determine whether HTN-associated Ang II was important for ECM regulation in RPE. We found that mouse RPE expressed both Ang II receptor subtypes at the mRNA and protein levels. Infusion with Ang II induced HTN and elevated plasma and ocular Ang II levels. Ang II also regulated AT1a and AT1b receptor mRNA expression, the intracellular concentration of calcium [Ca2+]i, MMP-2 activity, and type IV collagen accumulation. 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. Since the effects of Ang II on MMP-2 and type IV collagen require inhibition of both Ang II receptor subtypes, these receptors may play a role as a potential therapeutic targets to prevent ECM turnover dysregulation in the RPE basement membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD.
登录
查看更多内容
DOI：
10.1007/s00417-002-0615-3
发表时间：
2003-02-01
影响因子：
2.7
作者：
Jonas, JB;Hayreh, SS;Martus, P
通讯作者：
Martus, P
影响因子：
2
作者：
BRANDT, CR;PUMFERY, AM;WALLOW, IHL
通讯作者：
WALLOW, IHL
影响因子：
19.6
作者：
DEGASPARO, M;LEVENS, NR
通讯作者：
LEVENS, NR
影响因子：
4.4
作者：
Cousins, SW;Marin-Castaño, ME;Elliot, S
通讯作者：
Elliot, S
DOI：
10.1016/0006-291x(92)92384-a
发表时间：
1992-10-15
影响因子：
3.1
作者：
IWAI, N;INAGAMI, T;KINOSHITA, M
通讯作者：
KINOSHITA, M