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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 system.

Investigators with authorship
Name Institution Nobuyo Maeda University of North Carolina Oliver Smithies University of North Carolina Nobuyuki Takahashi Tohoku University

Complications
All ComplicationsBioinformatics BoneCardiomyopathy CardiovascularGastro-Intestinal (GI) NephropathyNeuropathy & Neurocognition Pediatric Endocrinology Retinopathy UropathyWound Healing