Atrial natriuretic peptide is eliminated from the brain by natriuretic peptide receptor-C-mediated brain-to-blood efflux transport at the blood-brain barrier

Shingo Ito, Sumio Ohtsuki, Yuki Katsukura, Miho Funaki, Yusuke Koitabashi, Akihiko Sugino, Sho Murata, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Cerebral atrial natriuretic peptide (ANP), which is generated in the brain, has functions in the regulation of brain water and electrolyte balance, blood pressure and local cerebral blood flow, as well as in neuroendocrine functions. However, cerebral ANP clearance is still poorly understood. The purpose of this study was to clarify the mechanism of blood-brain barrier (BBB) efflux transport of ANP in mouse. Western blot analysis showed expression of natriuretic peptide receptor (Npr)-A and Npr-C in mouse brain capillaries. The brain efflux index (BEI) method confirmed elimination of 125 Ihuman ANP (hANP) from mouse brain across the BBB. Inhibition studies suggested the involvement of Npr-C in vivo. Furthermore, rapid internalization of 125 IhANP by TM-BBB4 cells (an in vitro BBB model) was significantly inhibited by Npr-C inhibitors and by two different Npr-C-targeted short interfering RNAs (siRNAs). Finally, treatment with 1α,25-dihydroxyvitamin D3 (1,25(OH)2 D3) significantly increased Npr-C expression in TM-BBB4 cells, as determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted absolute proteomics. Our results indicate that Npr-C mediates brain-to-blood efflux transport of ANP at the mouse BBB as a pathway of cerebral ANP clearance. It seems likely that levels of natriuretic peptides in the brain are modulated by 1,25(OH)2 D3 through upregulation of Npr-C expression at the BBB.

Original languageEnglish
Pages (from-to)457-466
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number2
DOIs
Publication statusPublished - 2011 Feb

Keywords

  • atrial natriuretic peptide
  • blood-brain barrier
  • endothelium
  • natriuretic peptide receptor
  • receptors
  • vascular biology
  • vitamin D

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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