Abstract
Both epithelial-to-mesenchymal (EMT) and endothelial-to-mesenchymal (EndMT) transitions have shown to contribute to the development and progression of kidney fibrosis. It has been reported that apelin, a regulatory peptide, alleviates EMT by inhibiting the transforming growth factor β (TGFβ) pathway in renal diseases. Additionally, fibroblast growth factor receptor 1 (FGFR1) has been shown to be a key inhibitor of EndMT through suppression of the TGFβ/Smad pathway. In this study, we found that apelin and FGFR1 were spatially close to each other and that the apelin and FGFR1 complex displayed inhibitory effects on TGFβ/Smad signaling as well as associated EndMT in diabetic kidney fibrosis. In cultured human dermal microvascular endothelial cells (HMVECs), we found that the anti-EndMT and anti-TGFβ/Smad effects of apelin were dampened in FGFR1-deficient cells. Either siRNA- or an inhibitor-mediated deficiency of apelin induced the Smad3 phosphorylation and EndMT. Streptozotocin-induced CD-1 diabetic mice displayed EndMT and associated kidney fibrosis, which were restored by apelin treatment. The medium from apelin-deficient endothelial cells stimulated TGFβ/Smad-dependent EMT in cultured HK2 cells. In addition, depletion of apelin and the FGFR1 complex impaired CEBPA expression, and TGFβ-induced repression of CEBPA expression contributed to the initiation of EndMT in the endothelium. Collectively, these findings revealed that the interaction between apelin and FGFR1 displayed renoprotective potential through suppression of the TGFβ/Smad/CEBPA-mediated EndMT/EMT pathways.