Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na+/K+-ATPase-α-1

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Toledo
  • BloodCenter of Wisconsin
  • Marshall University
  • Cleveland Clinic Foundation

Details

Original languageEnglish (US)
Article numbere013933
JournalJournal of the American Heart Association
Volume9
Issue number3
StatusPublished - Feb 4 2020
Peer-reviewedYes

Abstract

Background: Recent studies have highlighted a critical role for a group of natriuretic hormones, cardiotonic steroid (CTS), in mediating renal inflammation and fibrosis associated with volume expanded settings, such as chronic kidney disease. Immune cell adhesion is a critical step in the inflammatory response; however, little is currently understood about the potential regulatory role of CTS signaling in this setting. Herein, we tested the hypothesis that CTS signaling through Na+/K+-ATPase α-1 (NKA α-1) enhances immune cell recruitment and adhesion to renal epithelium that ultimately advance renal inflammation. Methods and Results: We demonstrate that knockdown of the α-1 isoform of Na/K-ATPase causes a reduction in CTS-induced macrophage infiltration in renal tissue as well reduces the accumulation of immune cells in the peritoneal cavity in vivo. Next, using functional adhesion assay, we demonstrate that CTS-induced increases in the adhesion of macrophages to renal epithelial cells were significantly diminished after reduction of NKA α-1 in either macrophages or renal epithelial cells as well after inhibition of NKA α-1-Src signaling cascade with a specific peptide inhibitor, pNaKtide in vitro. Finally, CTS-induced expression of adhesion markers in both endothelial and immune cells was significantly inhibited in an NKA α-1-Src signaling dependent manner in vitro. Conclusions: These findings suggest that CTS potentiates immune cell migration and adhesion to renal epithelium through an NKA α-1–dependent mechanism; our new findings suggest that pharmacological inhibition of this feed-forward loop may be useful in the treatment of renal inflammation associated with renal disease.

    Research areas

  • Na/K-ATPase, adhesion, cardiotonic steroids, macrophage, renal epithelium, renal inflammation

Citation formats

APA

Khalaf, F. K., Tassavvor, I., Mohamed, A., Chen, Y., Malhotra, D., Xie, Z., ... Kennedy, D. J. (2020). Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na+/K+-ATPase-α-1. Journal of the American Heart Association, 9(3), [e013933]. https://doi.org/10.1161/JAHA.119.013933

Harvard

Khalaf, FK, Tassavvor, I, Mohamed, A, Chen, Y, Malhotra, D, Xie, Z, Tian, J, Haller, ST, Westfall, K, Tang, WHW & Kennedy, DJ 2020, 'Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na+/K+-ATPase-α-1', Journal of the American Heart Association, vol. 9, no. 3, e013933. https://doi.org/10.1161/JAHA.119.013933