Cellular Biology in Renal Diseases Laboratory. School of Medicine, Universidad Autónoma Madrid, Madrid, Spain.
Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
J Pathol. 2018 Feb;244(2):227-241. doi: 10.1002/path.5007. Epub 2018 Jan 10.
Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial-mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C-terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid-induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2-mediated profibrotic effects in renal diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
结缔组织生长因子（CCN2/CTGF）是一种基质细胞蛋白，在进行性人类肾脏疾病中过度表达，主要在纤维化区域。体外研究表明，CCN2 调节细胞外基质（ECM）蛋白的产生和上皮-间充质转化（EMT），因此可能有助于肾脏纤维化。CCN2 阻断可改善实验性肾损伤，包括减少 ECM 积聚。我们已经报道 CCN2 及其 C 末端降解产物 CCN2（IV）与表皮生长因子受体（EGFR）结合，以调节肾脏炎症。然而，到目前为止，尚未描述参与 CCN2 促纤维化作用的受体。使用 CCN2（IV）全身给药的小鼠模型，我们揭示了肾脏中的纤维化反应，该反应通过 EGFR 阻断而减轻。此外，在条件性 CCN2 敲除小鼠中，叶酸诱导的肾损伤引起的肾纤维化被预防，这与抑制 EGFR 途径激活有关。我们的体外研究表明，CCN2 通过 EGFR 途径对成纤维细胞 ECM 产生和肾小管上皮细胞 EMT 的诱导具有直接作用。我们的研究清楚地表明，EGFR 调节肾脏中 CCN2 的纤维化信号，并且提示 EGFR 途径阻断可能是阻断 CCN2 介导的肾脏疾病中促纤维化作用的潜在治疗选择。版权所有©2017 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd. 出版。
