Connective tissue growth factor plays an important role in advance glycation end product-induced tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease
Connective tissue growth factor plays an important role in advance glycation end product-induced tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease
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DOI：
10.1681/asn.2006050525
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发表时间：
2006-09-01
影响因子：
13.6
通讯作者：
Kantharidis, Phillip
中科院分区：
文献类型：
--
作者：
Burns, Wendy C.;Twigg, Stephen M.;Kantharidis, Phillip
肾小管上皮细胞向间充质细胞转化（EMT）有助于与糖尿病肾病相关的基质蛋白在肾脏的积聚。TGF-β 1和晚期糖基化终产物（AGE）都能够诱导细胞培养中的EMT。本研究探讨了前列腺生长因子结缔组织生长因子（CTGF）作为这些过程的下游介质的作用。通过α-平滑肌肌动蛋白、波形蛋白、E-钙粘蛋白和基质蛋白的表达以及成肌纤维细胞表型的诱导来评估EMT。在腺病毒中或作为重组人CTGF（250 ng/ml）递送的CTGF显示诱导部分EMT。这并不被中和性抗TGF-β 1抗体阻断，表明这种作用是不依赖于TGF-β 1的。暴露于AGE修饰的BSA（AGE-BSA; 40 μ M）或TGF-β 1（10 ng/ml）的NRK-52 E细胞也经历EMT。这与CTGF基因和蛋白表达的诱导有关。用siRNA转染CTGF能够减弱AGE或TGF-β 1治疗后EMT相关的表型变化。这些体外作用与体内发现的糖尿病肾脏中CTGF表达增加相关，CTGF表达在肾小管上皮细胞上与EMT位点共定位。此外，抑制AGE积累能够减少CTGF表达，减轻实验性糖尿病肾纤维化。这些发现表明，CTGF是肾小管EMT的重要独立介质，位于AGE或TGF-β 1作用的下游。这种相互作用可能在进行性糖尿病肾病中发挥重要作用，并加强了将CTGF视为糖尿病肾病治疗的潜在靶点的理由。
Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-beta 1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of a-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-beta 1 antibodies, suggesting that this action was TGF-beta 1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 mu M) or TGF-beta 1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-beta 1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-beta 1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.