Pregnancy-induced hypertension increases maternal and neonatal morbidity and mortality, but the underlying cause is poorly understood. Corin is a newly-discovered protease. It converts pro-atrial natriuretic peptide (pro-ANP) to active ANP, a cardiac hormone that regulates blood pressure. Corin knockout mice develop hypertension, indicating the importance of corin in maintaining normal blood pressure. In humans, corin variants are associated with an increased risk for hypertension and cardiac hypertrophy in African Americans. Unexpectedly, we found high levels of corin expression in the pregnant uterus and placenta in mice, suggesting a potential role of corin in pregnancy. We showed that blood pressure increased in pregnant corin null mice but returned to pre-pregnancy levels after delivery. The mice also had late gestational proteinuria, a phenotype reminiscent of preeclampsia in humans. Thus, corin may play an important role in the uterus to prevent hypertension during pregnancy and corin deficiency may contribute to pregnancy-induced hypertension. In this study, we will test this hypothesis in mouse models.
In Aim 1, we plan to determine the role of uterine corin in preventing pregnancy-induced hypertension.
In Aim 2, we plan to determine the role of uterine ANP production in preventing pregnancy-induced hypertension.
In Aim 3, we plan to determine the role of uterine corin-mediated ANP production in regulating spiral artery remodeling. The results from our studies may provide new insights into the pathogenesis of pregnancy-induced hypertension. If our hypothesis is validated, strategies to enhance the corin-mediated pathway may be developed to treat patients with preeclampsia.

Public Health Relevance

High blood pressure, or hypertension, during pregnancy poses a great danger to both the mother and the fetus. The disease happens in ~10% all pregnancies, but the exact cause is not known. Recently, we discovered a new molecule, corin, from the heart that keeps normal blood pressure. In mice lacking corin, blood pressure increased during pregnancy. The pregnant mice also had high protein contents in the urine, a condition similar to patients with pregnancy-induced hypertension. Our results indicate that corin is important in preventing high blood pressure during pregnancy. In this study, we will try to understand how corin works and if we can develop new corin-based methods to diagnose and treat high blood pressure during pregnancy. 1

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD064634-03
Application #
8435303
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$316,611
Indirect Cost
$114,948
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Theilig, Franziska; Wu, Qingyu (2015) ANP-induced signaling cascade and its implications in renal pathophysiology. Am J Physiol Renal Physiol 308:F1047-55
Chen, Shenghan; Cao, Pengxiu; Dong, Ningzheng et al. (2015) PCSK6-mediated corin activation is essential for normal blood pressure. Nat Med 21:1048-53
Song, Wei; Wang, Hao; Wu, Qingyu (2015) Atrial natriuretic peptide in cardiovascular biology and disease (NPPA). Gene 569:1-6
Li, Hui; Zhang, Yue; Wang, Lina et al. (2015) A novel cytoplasmic tail motif regulates mouse corin expression on the cell surface. Biochem Biophys Res Commun 465:152-8
Zhou, Yiqing; Wu, Qingyu (2014) Corin in natriuretic peptide processing and hypertension. Curr Hypertens Rep 16:415
Dong, Ningzheng; Zhou, Tiantian; Zhang, Yue et al. (2014) Corin mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting. [Corrected]. J Biol Chem 289:17909-16
Zhou, Y; Wu, Q (2013) Role of corin and atrial natriuretic peptide in preeclampsia. Placenta 34:89-94
Wang, Wei; Cui, Yujie; Shen, Jianzhong et al. (2012) Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks. Hypertension 60:1352-8
Dong, Ningzheng; Chen, Shenghan; Wang, Wei et al. (2012) Corin in clinical laboratory diagnostics. Clin Chim Acta 413:378-83

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