期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 14, 期 6B, 页码 1857-1867出版社
WILEY
DOI: 10.1111/j.1582-4934.2009.00820.x
关键词
preeclampsia; vascular endothelial growth factor; fms-like tyrosine kinase receptor; vascular disease
资金
- German Research Council (DFG) [We1211/5-3 + 7-1]
- Medical Research Council [G0601295, G00700288]
- MRC [G0601295, G0700288] Funding Source: UKRI
- Medical Research Council [G0700288, G0601295] Funding Source: researchfish
Preeclampsia (PE) is characterized by widespread endothelial damage with hypertension, proteinuria, glomeruloendotheliosis and elevated soluble Flt-1 (sFlt-1), a natural occurring antagonist of vascular endothelial growth factor (VEGF). Cancer patients receiving anti-VEGF therapy exhibit similar symptoms. We suggested that a decrease in circulating sFlt-1 would alleviate the symptoms associated with PE. Adenoviral (Adv) overexpression of sFlt-1 induced proteinuria, caused glomerular damage and increase in blood pressure in female Balb/c mice. Circulating level of sFlt-1 above 50 ng/ml plasma induced severe vascular damage and glomerular endotheliosis. Albumin concentration in urine was elevated up to 30-fold, compared to control AdvGFP-treated animals. The threshold of kidney damage was in the range of 20-30 ng/ml sFlt-1 in plasma (8-15 ng/ml in urine). Co-administration of AdvsFlt-1 with AdvVEGF to neutralize circulating sFlt-1 resulted in more than a 70% reduction in free sFlt-1 in plasma, more than 80% reduction in urine and rescued the damaging effect of sFlt-1 on the kidneys. This demonstrates that below a critical threshold sFlt-1 fails to elicit damage to the fenestrated endothelium and that co-expression of VEGF is able to rescue effects mediated by sFlt-1 overexpression.
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