Ito Yasuhiko, Goldschmeding Roel, Bende Richard J, Claessen Nike, Chand M Anwar, Kleij Livio, Rabelink Ton J, Weening Jan J, Aten Jan
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Internal Medicine, Chubu Rousai Hospital, Nagoya, Japan.
J Am Soc Nephrol. 2001 Mar;12(3):472-484. doi: 10.1681/ASN.V123472.
Connective tissue growth factor (CTGF) is a member of the CCN family of immediate early genes, which are involved in cell proliferation, migration, and matrix production. Recently, CTGF was observed to be strongly upregulated in human proliferative and fibrogenic renal disease. By in situ hybridization and reverse transcriptase-PCR, the expression of CTGF was investigated in experimental proliferative glomerulonephritis induced by injection of anti-Thy-1.1 antibody in the rat. CTGF expression in cultured rat mesangial cells and glomerular visceral epithelial cells (GVEC) was studied in response to transforming growth factor beta (TGF-beta), an essential pathogenetic factor in this model. In normal rat kidneys, only some GVEC expressed CTGF mRNA. In anti-Thy-1.1 nephritis, CTGF mRNA expression was strongly increased in extracapillary and mesangial proliferative lesions and in areas of periglomerular fibrosis. Early glomerular CTGF overexpression in GVEC coincided with a striking upregulation of TGF-beta2 and to a lesser extent of TGF-beta3. Glomerular CTGF mRNA expression was maximal at day 7, in association with increased TGF-beta1 mRNA and protein expression. CTGF mRNA overexpression by parietal epithelial cells preceded the periglomerular appearance of alpha-smooth muscle actin-positive fibroblasts. In cultured mesangial cells, TGF-beta1, -beta2, and -beta3 transiently increased the CTGF/glyceraldehyde phosphate dehydrogenase mRNA ratio up to threefold versus control at 4 h. In GVEC, upregulation of CTGF mRNA by these TGF-beta isoforms was more sustained, being 8- to 16-fold versus control at 24 h. The kinetics of CTGF expression strongly suggest a role in glomerular repair, possibly downstream of TGF-beta, in this model of transient renal injury.
结缔组织生长因子（CTGF）是即刻早期基因CCN家族的成员，该家族参与细胞增殖、迁移和基质产生。最近，人们观察到CTGF在人类增殖性和纤维化肾病中强烈上调。通过原位杂交和逆转录聚合酶链反应，在大鼠中注射抗Thy-1.1抗体诱导的实验性增殖性肾小球肾炎中研究了CTGF的表达。研究了培养的大鼠系膜细胞和肾小球脏层上皮细胞（GVEC）中CTGF的表达，以响应转化生长因子β（TGF-β），TGF-β是该模型中的一个重要致病因子。在正常大鼠肾脏中，只有一些GVEC表达CTGF mRNA。在抗Thy-1.1肾炎中，CTGF mRNA表达在毛细血管外和系膜增殖性病变以及肾小球周围纤维化区域中强烈增加。GVEC中早期肾小球CTGF过表达与TGF-β2的显著上调以及程度较轻的TGF-β3上调同时发生。肾小球CTGF mRNA表达在第7天达到最大值，与TGF-β1 mRNA和蛋白表达增加相关。壁层上皮细胞CTGF mRNA过表达先于α-平滑肌肌动蛋白阳性成纤维细胞在肾小球周围出现。在培养的系膜细胞中，TGF-β1、-β2和-β3在4小时时使CTGF/甘油醛-3-磷酸脱氢酶mRNA比值相对于对照瞬时增加高达三倍。在GVEC中，这些TGF-β同工型对CTGF mRNA的上调更持久，在24小时时相对于对照为8至16倍。CTGF表达的动力学强烈表明其在该短暂性肾损伤模型的肾小球修复中起作用，可能在TGF-β的下游。
