Abstract
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. We have reported that N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP) restored levels of diabetes mellitus-suppressed FGFR1 (fibroblast growth factor receptor 1), the endothelial receptor essential for combating EndMT. However, the molecular regulation and biological/pathological significance of the AcSDKP-FGFR1 relationship has not been elucidated yet. Here, we demonstrated that endothelial FGFR1 deficiency led to AcSDKP-resistant EndMT and severe fibrosis associated with EndMT-stimulated fibrogenic programming in neighboring cells. Diabetes mellitus induced severe kidney fibrosis in endothelial FGFR1-deficient mice (FGFR1fl/fl; VE-cadherin-Cre: FGFR1EKO) but not in control mice (FGFR1fl/fl); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1EKO mice. Severe fibrosis was also induced in hearts of diabetic FGFR1EKO mice; however, AcSDKP had no effect on heart fibrosis in FGFR1EKO mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1EKO mice. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelial-to-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-to-mesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP.
Highlights
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis
Endothelial-specific FGFR1 knockout mice (FGFR1EKO; C57BL/6J background) were generated by crossing VE-cadherin-Cre recombinase-positive (Cdh5-Cre) mice (NIBIOHN, Osaka, Japan) and FGFR1 loxP/loxP floxed (FGFR1fl/fl) mice with genes flanked by the loxP sites of exon 4
To determine the pathological significance of endothelial FGFR1 in the diabetic kidney and heart, we first generated conditional endothelial knockout mice by crossing mice with FGFR1 genes flanked by loxP sites (FGFR1fl/fl) with VE-cadherin-Cre transgenic mice (FGFR1EKO: FGFR1fl/fl; VE-cadherinCre; Figure S1 in the Data Supplement)
Summary
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelialto-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-tomesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a tetrapeptide derived from the N-terminal sequence of Tβ4 (thymosinβ4),[19,20,21,22,23] has been shown to display the anti-EndMT and antifibrotic effects.[6,24,25,26,27,28,29,30,31,32,33] In the kidneys and hearts of diabetic mice, AcSDKP restored the decreased endothelial FGFR level.[6] We have confirmed that endothelial FGFR1 is essential. The significance of endothelial FGFR1 as the antifibrotic target of AcSDKP in vivo setting was not elucidated yet
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