Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction
Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction
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DOI：
10.1038/ki.2011.464
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发表时间：
2012-05-01
影响因子：
19.6
通讯作者：
Takei, Yoshifumi
中科院分区：
文献类型：
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作者：
Suzuki, Yasuhiro;Ito, Yasuhiko;Takei, Yoshifumi
炎症被认为是淋巴管生成的重要因素；然而，在人类慢性肾脏疾病的肾小管间质病变中，这一过程与肌成纤维细胞而不是巨噬细胞的存在更好地相关。由于对淋巴管生成和肾纤维化之间的相互作用知之甚少，我们利用大鼠单侧输尿管梗阻模型来分析炎症、纤维化、淋巴管生成和生长因子表达。此外，我们还确定了血管内皮生长因子-C (VEGF-C)（一种淋巴管生成诱导剂）与促纤维化因子、转化生长因子-β 1 (TGF-β 1) 之间的关系。肾小管上皮细胞和单核细胞中均检测到TGF-β1和VEGF-C的表达，并逐渐升高，在输尿管梗阻后14天达到高峰。 VEGF-C 的动力学和定位与 TGF-β 1 相似，这些生长因子的表达和淋巴管生成与纤维化的进展有关。在培养的近端肾小管上皮细胞、集合管细胞和巨噬细胞中，TGF-β1 上调 VEGF-C 表达。在体外和体内，VEGF-C 的诱导以及体内淋巴管的整体外观均被 TGF-β I 型受体抑制剂 LY364947 特异性抑制。因此，TGF-1 诱导 VEGF-C 表达，从而导致淋巴管生成。肾脏国际 (2012) 81, 865-879; doi：10.1038/ki.2011.464； 2012 年 1 月 18 日在线发布
Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-beta 1 (TGF-beta 1). The expression of both TGF-beta 1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-beta 1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-beta 1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-beta type I receptor inhibitor LY364947. Thus, TGF-1 induces VEGF-C expression, which leads to lymphangiogenesis. Kidney International (2012) 81, 865-879; doi:10.1038/ki.2011.464; published online 18 January 2012