期刊
KIDNEY INTERNATIONAL
卷 85, 期 2, 页码 393-403出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2013.339
关键词
atherosclerosis; chronic kidney disease; placental growth factor; soluble fms-like tyrosine kinase-1
资金
- Merck
- Takeda Pharmaceutical Company
- Novartis Pharma KK
- Daiichi Sankyo Company
- Mitsubishi Tanabe Pharma Corporation
- Pfizer Japan
- Otsuka Pharmaceutical
- Takeda Pharmaceutical Company Limited
- Astellas Pharma
- Baxter
- AstraZeneca KK
- Shionogi
- Grants-in-Aid for Scientific Research [25461226, 24659415] Funding Source: KAKEN
Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PIGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PIGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PIGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.
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