Abstract
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.
Highlights
IntroductionCellular communication network-2 (CCN2), called connective tissue growth factor (CTGF), is a member of the CCN family and shares many properties with other CCN proteins [1,2]
epidermal growth factor receptor (EGFR) binds to multiple ligands, being relevant in kidney diseases, mainly EGF, transforming growth factor (TGF)-α, heparin-binding EGF-like growth factor (HB-EGF) [7,40,42], amphiregulin [44], and, as we have previously described, communication network-2 (CCN2) [34]
In previous studies, using an EGFR kinase inhibitor, we have described that CCN2-induced profibrotic responses in the kidney [21], endothelial dysfunction, and vascular inflammation [45] were mediated by EGFR signaling pathway activation
Summary
Cellular communication network-2 (CCN2), called connective tissue growth factor (CTGF), is a member of the CCN family and shares many properties with other CCN proteins [1,2]. Intensive research in the last years has unraveled the complexity of the CCN family. All CCN family members are matricellular proteins, key components of the extracellular matrix (ECM), that contain multiple ligand and receptor binding sites and are actively involved in cellular communication and signaling. Key differences between them have been described, with CCN2 being especially relevant in renal diseases [3,4]. Key differences between them have been described, with CCN2 being especially relevant in renal diseases [3,4]. 4.0/).
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