CCN2 Binds to Tubular Epithelial Cells in the Kidney.
CCN2 Binds to Tubular Epithelial Cells in the Kidney.
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DOI：
10.3390/biom12020252
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发表时间：
2022-02-03
期刊：
影响因子：
5.5
通讯作者：
Ruiz-Ortega M
中科院分区：
文献类型：
--
作者：
Rayego-Mateos S;Morgado-Pascual JL;Lavoz C;Rodrigues-Díez RR;Márquez-Expósito L;Tejera-Muñoz A;Tejedor-Santamaría L;Rubio-Soto I;Marchant V;Ruiz-Ortega M
细胞通讯网络 2 (CCN2)，也称为结缔组织生长因子 (CTGF)，被认为是纤维化生物标志物，并被建议作为肾脏病理的潜在治疗靶点。 CCN2是一种基质细胞蛋白，具有四个不同的结构模块，可以发挥基质细胞蛋白和生长因子的双重功能。先前使用表面等离振子共振和培养肾细胞的实验已证明CCN2 (CCN2(IV)) 的C末端模块与表皮生长因子受体(EGFR)相互作用。此外，CCN2(IV) 还可激活小鼠肾脏中的促炎和促纤维化反应。本文的目的是定位肾脏中的体内细胞 CCN2/EGFR 结合位点。为此，C 端模块 CCN2(IV) 用荧光团 (Cy5) 标记，并采用两种不同的给药途径。小鼠腹腔内和直接肾内注射 Cy5-CCN2(IV) 均表明 CCN2(IV) 优先与肾小管上皮细胞结合，而在肾小球中未检测到信号。此外，在肾小管中发现了 Cy5-CCN2(IV) 结合和激活的 EGFR 的共定位。在培养的肾小管上皮细胞中，活细胞共聚焦显微镜实验表明，EGFR 基因沉默可阻断 Cy5-CCN2(IV) 与肾小管上皮细胞的结合。这些数据清楚地表明肾脏中（主要是肾小管上皮细胞）中存在CCN2/EGFR结合位点。总之，这些研究表明循环中的 CCN2(IV) 可以直接结合并激活肾小管细胞，支持 CCN2 作为生长因子参与肾脏损伤进展的作用。
Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual function as a matricellular protein and as a growth factor. Previous experiments using surface plasmon resonance and cultured renal cells have demonstrated that the C-terminal module of CCN2 (CCN2(IV)) interacts with the epidermal growth factor receptor (EGFR). Moreover, CCN2(IV) activates proinflammatory and profibrotic responses in the mouse kidney. The aim of this paper was to locate the in vivo cellular CCN2/EGFR binding sites in the kidney. To this aim, the C-terminal module CCN2(IV) was labeled with a fluorophore (Cy5), and two different administration routes were employed. Both intraperitoneal and direct intra-renal injection of Cy5-CCN2(IV) in mice demonstrated that CCN2(IV) preferentially binds to the tubular epithelial cells, while no signal was detected in glomeruli. Moreover, co-localization of Cy5-CCN2(IV) binding and activated EGFR was found in tubules. In cultured tubular epithelial cells, live-cell confocal microscopy experiments showed that EGFR gene silencing blocked Cy5-CCN2(IV) binding to tubuloepithelial cells. These data clearly show the existence of CCN2/EGFR binding sites in the kidney, mainly in tubular epithelial cells. In conclusion, these studies show that circulating CCN2(IV) can directly bind and activate tubular cells, supporting the role of CCN2 as a growth factor involved in kidney damage progression.
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