Editors' ChoiceCell Biology

Finding a missing link in blood pressure regulation

Sci. Signal.  22 Sep 2015:
Vol. 8, Issue 395, pp. ec271
DOI: 10.1126/scisignal.aad4563

Imbalance of sodium homeostasis is a leading cause of hypertension. Atrial natriuretic peptide (ANP), a hormone released by the heart, acts on the kidneys to promote sodium excretion. In cardiomyocytes, ANP is produced by the cleavage of its precursor form, pro-ANP, by a serine protease called corin. Corin is also produced as a zymogen that must be activated by protease-mediated cleavage. Chen et al. identified a protease responsible for corin activation. Western blot analysis of human embryonic kidney (HEK) 293 cells transfected with wild-type corin and exposed to a nonspecific serine protease inhibitor, a nonspecific cysteine protease inhibitor, or a nonspecific inhibitor of arginine proteases [Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVLR-cmk)] showed that only exposure to the dec-RVLR-cmk reduced the abundance of the cleaved and activated form of corin. The PCSK (proprotein convertase subtilisin/kexin) family of proteases are arginine-directed proteases and corin must be cleaved between Arg801 and Ile802; therefore, the authors tested if a PCSK cleaved corin by coexpressing individual PCSK family members and the corin zymogen in HEK293 cells and analyzing the abundance of the cleaved and zymogen forms of corin by Western blotting. Only coexpression with PCSK6 reduced the abundance of the zymogen. Pro-ANP abundance was higher in the hearts of mice in which PCSK6 or Corin was knocked out compared with its abundance in the hearts of wild-type controls. Pcsk6-knockout mice became hypertensive even when kept on a normal sodium diet, which indicated that PCSK6-mediated corin activation is essential for blood pressure regulation, likely through control of sodium homeostasis. The authors sequenced PCSK6 gene from 100 hypertensive individuals and identified a D282N mutation in the catalytic domain of PCSK6 in one person. HEK293 cells transfected with the PCSK6 D282N mutant showed reduced cleaved corin. These findings suggest that PCSK6 is a primary physiological activator of corin zymogen, thereby filling in a missing piece in the regulation of sodium homeostasis.

S. Chen, P. Cao, N. Dong, J. Peng, C. Zhang, H. Wang, T. Zhou, J. Yang, Y. Zhang, E. E. Martelli, S. V. N. Prasad, R. E. Miller, A.-M. Malfait, Y. Zhou, Q. Wu, PCSK6-mediated corin activation is essential for normal blood pressure. Nat. Med. 21, 1048–1053 (2015). [PubMed]

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