Open AccessReduction of circulating soluble Flt‐1 alleviates preeclampsia‐like symptoms in a mouse model
Author(s) -
Bergmann Astrid,
Ahmad Shakil,
Cudmore Melissa,
Gruber Achim D.,
Wittschen Petra,
Lindenmaier Werner,
Christofori Gerhard,
Gross Volkmar,
Gonzalves Andrey Ch. da Costa,
Gröne HermannJosef,
Ahmed Asif,
Weich Herbert A.
Publication year - 2010
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00820.x
Subject(s) - proteinuria , preeclampsia , endocrinology , medicine , albuminuria , vascular endothelial growth factor , urine , kidney , endothelium , albumin , biology , vegf receptors , pregnancy , genetics
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.