期刊
HYPERTENSION
卷 76, 期 6, 页码 1935-1944出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.120.15587
关键词
diabetes mellitus; endothelial cells; fibrosis; thymosin; vimentin
资金
- Japan Diabetes Foundation
- Japan Society for the Promotion of Science [23790381, 25282028, 25670414]
- Kanazawa Medical University [C2011-4, C2012-1, S2015-3, S2016-3, S2017-1]
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 (FGFR1(fl/fl); VE-cadherin-Cre: FGFR1(EKO)) but not in control mice (FGFR1(fl/fl)); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1(EKO) mice. Severe fibrosis was also induced in hearts of diabetic FGFR1(EKO) mice; however, AcSDKP had no effect on heart fibrosis in FGFR1(EKO) mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1(EKO) mice. The medium from FGFR1-deficient endothelial cells stimulated TGF beta (transforming growth factor beta)/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.
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