Abstract

Hypertension is the most common cardiovascular disease, afflicting >30% of adults1. The cause of hypertension in most individuals remains unknown2,3, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure4. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia5,6,7,8,9. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.

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Acknowledgements

We thank M. Yin of the Lerner Imaging Core at the Cleveland Clinic for electron microscopic analysis and W. Claycomb of Louisiana State University Medical Center for HL-1 cells. This work was supported in part by grants from the US National Institutes of Health (R01HL089298, R01HD064634, R01HL126697) (Q.W.), a Rush University Pilot Grant (A.-M.M.), the National Natural Science Foundation of China (81170247, 81370718) (N.D.), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Author information

Author notes

    • Shenghan Chen
    • , Pengxiu Cao
    •  & Chunyi Zhang

    Present addresses: Department of Gynecology and Obstetrics, Jiangxi Provincial People's Hospital, Nanchang, China (S.C.); Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA (P.C.); Biochemistry and Molecular Biology Department, Shanghai Medical School, Fudan University, Shanghai, China (C.Z.).

Affiliations

  1. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Shenghan Chen
    • , Pengxiu Cao
    • , Jianhao Peng
    • , Chunyi Zhang
    • , Hao Wang
    • , Elizabeth E Martelli
    • , Sathyamangla V Naga Prasad
    •  & Qingyu Wu
  2. Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.

    • Ningzheng Dong
    • , Tiantian Zhou
    • , Yue Zhang
    • , Yiqing Zhou
    •  & Qingyu Wu
  3. Key Laboratory of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China.

    • Ningzheng Dong
  4. Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China.

    • Junhua Yang
  5. Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, Illinois, USA.

    • Rachel E Miller
    •  & Anne-Marie Malfait
  6. Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.

    • Rachel E Miller
    •  & Anne-Marie Malfait

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Contributions

S.C., P.C., N.D. and Q.W. designed the study. S.C., P.C., J.P., C.Z. and H.W. performed molecular biology, biochemistry, cell biology and mouse model studies. N.D., T.Z., J.Y. and Y. Zhang studied hypertensive patients, collected blood samples, sequenced PCSK6 exons, and made plasmids expressing corin variants. E.E.M. and S.V.N.P. did echocardiographic analysis in mice. R.E.M. and A.-M.M. provided Pcsk6-KO mice. S.C., Y. Zhou and Q.W. wrote the manuscript. All authors critically read and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Qingyu Wu.

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DOI

https://doi.org/10.1038/nm.3920

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