Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways
Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways
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DOI：
10.1016/s0002-9440(10)63659-0
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发表时间：
2003-07-01
影响因子：
6
通讯作者：
Mervaala, E
中科院分区：
文献类型：
--
作者：
Finckenberg, P;Inkinen, K;Mervaala, E
结缔组织生长因子（CTGF）是一种参与细胞外基质合成的多肽。先前的研究提供的证据表明，血管紧张素 II (Ang II) 可以促进胶原蛋白合成并调节胶原蛋白的降解。我们研究了 CTGF 是否介导 Ang H 在心脏和肾脏中的促纤维化作用，以及钙依赖磷酸酶依赖性途径在 CTGF 基因调控中的作用。在携带人肾素和血管紧张素原基因的转基因大鼠中，Ang H 诱导心肌 CTGF 表达呈年龄依赖性增加，与血压正常的 Sprague Dawley (SD) 大鼠相比，增加了 3.5 倍。 C-TGF 过度表达与 Ang H 诱导的血压升高密切相关。 CTGF mRNA 和蛋白主要位于白细胞浸润、心肌和血管病变区域，并与 TGFbeta(1)、胶原蛋白 I 和胶原蛋白 III mRNA 表达共定位。 Ang II 在肾脏中较小程度地诱导 CTGF mRNA 和蛋白质，主要是在肾小球、小动脉和具有充分炎症的间质中。然而，在右心室或肺动脉中未发现表达。环孢菌素 A 阻断钙调神经磷酸酶活性，使 Ang II 诱导的心脏和肾脏中 CTGF 过度表达完全正常化，抑制炎症反应，并减轻 Ang H 诱导的细胞增殖和凋亡。相比之下，尽管依维莫司改善了细胞增殖和T细胞介导的炎症，但依维莫司阻断mTOR（雷帕霉素靶标）途径进一步增加了CTGF的表达。我们的研究结果证明 CTGF 通过血压和钙调神经磷酸酶依赖性途径介导 Ang H 诱导的心脏和肾脏纤维化。
Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collage a degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang H in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang H induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. C-TGF overexpression correlated closely with the Ang H-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang H-induced cell proliferation and apoptosis. in contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang H-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.