eNOS deficiency acts through endothelin to aggravate sFlt-1-induced
pre-eclampsia-like phenotype.
Authors Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA,
Smithies O, Takahashi N
Submitted By Nobuyuki Takahashi on 8/1/2012
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2012
Date Published 4/1/2012
Volume : Pages 23 : 652 - 660
PubMed Reference 22282588
Abstract Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial
growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like
features by antagonizing vascular endothelial growth factor signaling, which can
lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of
this concomitant decrease in eNOS activity is unknown. We tested whether the
decrease in nitric oxide occurring in female mice lacking eNOS aggravates the
pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated
eNOS-deficient female mice had higher BP than wild-type mice.
Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by
approximately 27 mmHg and led to severe loss of fenestration of glomerular
capillary endothelial cells in both eNOS-deficient and wild-type mice. However,
only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement.
Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed
markedly higher urinary albumin excretion (467±74 versus 174±23 µg/d), lower
creatinine clearance (126±29 versus 452±63 µl/min), and more severe
endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET(A) receptor in
the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1
mice. Furthermore, the selective ET(A) receptor antagonist ambrisentan
attenuated the increases in BP and urinary albumin excretion and ameliorated
endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan
improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1
mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the
sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina
Oliver SmithiesUniversity of North Carolina
Nobuyuki TakahashiTohoku University