C Type Natriuretic Peptide Receptor Activation Inhibits Sodium Channel Activity in Human Aortic Endothelial Cells by Activating the Diacylglycerol-Protein Kinase C Pathway

Int J Mol Sci. 2022 Nov 12;23(22):13959. doi: 10.3390/ijms232213959.

Abstract

The C-type natriuretic peptide receptor (NPRC) is expressed in many cell types and binds all natriuretic peptides with high affinity. Ligand binding results in the activation or inhibition of various intracellular signaling pathways. Although NPRC ligand binding has been shown to regulate various ion channels, the regulation of endothelial sodium channel (EnNaC) activity by NPRC activation has not been studied. The objective of this study was to investigate mechanisms of EnNaC regulation associated with NPRC activation in human aortic endothelial cells (hAoEC). EnNaC protein expression and activity was attenuated after treating hAoEC with the NPRC agonist cANF compared to vehicle, as demonstrated by Western blotting and patch clamping studies, respectively. NPRC knockdown studies using siRNA's corroborated the specificity of EnNaC regulation by NPRC activation mediated by ligand binding. The concentration of multiple diacylglycerols (DAG) and the activity of protein kinase C (PKC) was augmented after treating hAoEC with cANF compared to vehicle, suggesting EnNaC activity is down-regulated upon NPRC ligand binding in a DAG-PKC dependent manner. The reciprocal cross-talk between NPRC activation and EnNaC inhibition represents a feedback mechanism that presumably is involved in the regulation of endothelial function and aortic stiffness.

Keywords: aortic endothelial cells; diacylglycerols; endothelial sodium channels; natriuretic peptide receptor C; protein kinase C.

MeSH terms

  • Diglycerides / metabolism
  • Diglycerides / pharmacology
  • Endothelial Cells* / metabolism
  • Humans
  • Ligands
  • Natriuretic Peptide, C-Type / metabolism
  • Natriuretic Peptides / metabolism
  • Protein Kinase C* / metabolism

Substances

  • atrial natriuretic factor receptor C
  • Protein Kinase C
  • Natriuretic Peptide, C-Type
  • Diglycerides
  • Ligands
  • Natriuretic Peptides