Clinical Investigation
Suppressed soluble Fms–like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease

https://doi.org/10.1038/ki.2013.339Get rights and content
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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 (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. 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 PlGF 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.

KEYWORDS

atherosclerosis
chronic kidney disease
placental growth factor
soluble fms-like tyrosine kinase-1

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YS received lecture fees from Merck, Takeda Pharmaceutical Company, Novartis Pharma KK, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Pfizer Japan, Otsuka Pharmaceutical, and research fundings from Merck, Takeda Pharmaceutical Company Limited, Novartis Pharma KK, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Pfizer Japan, Otsuka Pharmaceutical, Astellas Pharma, Baxter, AstraZeneca KK, Shionogi. YS and SS also belong to the endowed department (the Department of Regulatory Medicine of Blood Pressure) sponsored by Merck.

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These authors contributed equally to this work.

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Current address: Department of Nephrology, Fukui University, Japan.