eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype

Feng Li, John R. Hagaman, Hyung Suk Kim, Nobuyo Maeda, J. Charles Jennette, James E. Faber, S. Ananth Karumanchi, Oliver Smithies, Nobuyuki Takahashi

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

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 andwild-typemice. 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 ETA receptor in the kidney was higher in eNOS-deficient sFlt-1mice 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 system.

Original languageEnglish
Pages (from-to)652-660
Number of pages9
JournalJournal of the American Society of Nephrology
Volume23
Issue number4
DOIs
Publication statusPublished - 2012 Apr

ASJC Scopus subject areas

  • Nephrology

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