Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina.
Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina.
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DOI：
10.1007/s00125-007-0621-4
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发表时间：
2007-05
期刊：
影响因子：
8.2
通讯作者：
Schlingemann, R. O.
中科院分区：
文献类型：
--
作者：
Hughes, J. M.;Kuiper, E. J.;Klaassen, I.;Canning, P.;Stitt, A. W.;Van Bezu, J.;Schalkwijk, C. G.;Van Noorden, C. J. F.;Schlingemann, R. O.
关键词：
由富半胱氨酸蛋白61 （CYR61，也称为CCN1）、结缔组织生长因子（CTGF，也称为CCN2）、肾母细胞瘤过表达基因（NOV，也称为CCN3）和wnt1诱导的信号通路蛋白1、2和3 （WISP1、−2和−3，也称为CCN4、−5和−6）组成的生长因子家族，简称CCN，在伤口修复、纤维化疾病、炎症和血管生成中影响细胞的生长、分化、粘附和运动。在糖尿病环境中形成的AGEs影响相同的过程，导致糖尿病并发症，包括糖尿病视网膜病变。我们假设糖尿病视网膜中AGEs的病理作用是age诱导CCN家族表达改变的结果。采用实时定量PCR、western blotting和免疫组织化学方法，研究了在链脲霉素诱导的糖尿病大鼠视网膜中，在存在或不存在氨基胍（一种AGE抑制剂）的情况下，CCN基因mRNA和蛋白水平的表达水平。此外，在C57BL/6小鼠体内反复注射外源性形成的AGE，以确定AGE是否调节视网膜CCN生长因子。糖尿病患者6周后，Cyr61表达水平增加了3倍以上。在糖尿病12周时，Ctgf表达水平增加了两倍。氨基胍抑制了Cyr61和Ctgf在糖尿病大鼠中的表达，与未治疗的动物相比，分别降低了31%和36%。Western blotting显示CTGF的产生增加了两倍，氨基胍处理可以阻止CTGF的产生。在注入外源性AGE的小鼠中，Cyr61的表达增加了4倍，Ctgf的表达增加了2倍。CTGF和CYR61是糖尿病视网膜中AGE的下游效应物，这意味着它们可能是未来针对糖尿病视网膜病变发展的干预策略的目标。本文的在线版本（doi:10.1007/s00125-007-0621-4）包含补充材料，可供授权用户使用。
Referred to as CCN, the family of growth factors consisting of cystein-rich protein 61 (CYR61, also known as CCN1), connective tissue growth factor (CTGF, also known as CCN2), nephroblastoma overexpressed gene (NOV, also known as CCN3) and WNT1-inducible signalling pathway proteins 1, 2 and 3 (WISP1, −2 and −3; also known as CCN4, −5 and −6) affects cellular growth, differentiation, adhesion and locomotion in wound repair, fibrotic disorders, inflammation and angiogenesis. AGEs formed in the diabetic milieu affect the same processes, leading to diabetic complications including diabetic retinopathy. We hypothesised that pathological effects of AGEs in the diabetic retina are a consequence of AGE-induced alterations in CCN family expression. CCN gene expression levels were studied at the mRNA and protein level in retinas of control and diabetic rats using real-time quantitative PCR, western blotting and immunohistochemistry at 6 and 12 weeks of streptozotocin-induced diabetes in the presence or absence of aminoguanidine, an AGE inhibitor. In addition, C57BL/6 mice were repeatedly injected with exogenously formed AGE to establish whether AGE modulate retinal CCN growth factors in vivo. After 6 weeks of diabetes, Cyr61 expression levels were increased more than threefold. At 12 weeks of diabetes, Ctgf expression levels were increased twofold. Treatment with aminoguanidine inhibited Cyr61 and Ctgf expression in diabetic rats, with reductions of 31 and 36%, respectively, compared with untreated animals. Western blotting showed a twofold increase in CTGF production, which was prevented by aminoguanidine treatment. In mice infused with exogenous AGE, Cyr61 expression increased fourfold and Ctgf expression increased twofold in the retina. CTGF and CYR61 are downstream effectors of AGE in the diabetic retina, implicating them as possible targets for future intervention strategies against the development of diabetic retinopathy. The online version of this article (doi:10.1007/s00125-007-0621-4) contains supplementary material, which is available to authorised users.
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