| Autor: |
Rongfen Gao, Keizo Kanasaki, Jinpeng Li, Munehiro Kitada, Toshiro Okazaki, Daisuke Koya |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
FEBS Open Bio, Vol 9, Iss 5, Pp 1029-1038 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2211-5463 |
| DOI: |
10.1002/2211-5463.12638 |
| Popis: |
Endothelial–mesenchymal transition (EndMT) has emerged as an essential bioprocess responsible for the development of organ fibrosis. We have previously reported that fibroblast growth factor receptor 1 (FGFR1) is involved in the anti‐EndMT effect of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP). FGFR1 is expressed on the cell membrane and performs its biological function through interaction with co‐receptors, including βklotho (KLB). However, it remains unknown whether KLB is involved in the anti‐EndMT effects of AcSDKP. Here, we demonstrated that AcSDKP increased KLB expression in an FGFR1‐dependent manner and that KLB deficiency induced AcSDKP‐resistant EndMT via the induction of the mitogen‐activated protein kinase (MAPK) pathway. In cultured endothelial cells, AcSDKP increased KLB protein level in an FGFR1‐dependent manner through induction of the FGFR1–KLB complex. KLB suppression by small interfering RNA transfection did not affect FGFR1 levels and resulted in the induction of EndMT. In contrast to the EndMT observed under FGFR1 deficiency, the EndMT induced by KLB suppression was not accompanied by the induction of Smad3 phosphorylation; instead, KLB‐deficient cells exhibited induced activation of the MAPK/extracellular signal‐regulated kinase (ERK) kinase (MEK) and ERK pathways. Treatment with the specific MEK inhibitor U0126 diminished KLB deficiency‐induced EndMT. Consistent with this finding, AcSDKP did not suppress either EndMT or MEK/ERK activation induced by KLB deficiency. Application of either FGF19 or FGF21 synergistically augmented the anti‐EndMT effects of AcSDKP. Taken together, these results indicate that endogenous peptide AcSDKP exerts its activity through induction of the FGFR1–KLB complex in vascular endothelial cells. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Plný text