期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 23, 期 4, 页码 652-660出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2011040369
关键词
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资金
- American Heart Association [0265464U, 0855335E]
- National Institutes of Health [HL049277, U01 DK076131, HL077145, P30DK56350, P30 ES10126]
- Japan Society of Promotion of Science (JSPS) [22890016]
- Department of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill
- Japanese Society of Nephrology
- Research Group on Progressive Renal Disease from the Ministry of Health, Labor and Welfare, Japan
- Miyagi Association of Kidney Disease
- Banyu Life Science Foundation International
- Grants-in-Aid for Scientific Research [22890016, 24659409] Funding Source: KAKEN
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 mu g/d), lower creatinine clearance (126 +/- 29 versus 452 +/- 63 mu l/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ETA receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ETA receptor antagonist annbrisentan 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.
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