Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na+/K+-ATPase-α-1. J Am Heart Assoc 2020 Feb 04;9(3):e013933
Date
02/06/2020Pubmed ID
32013704Pubmed Central ID
PMC7033897DOI
10.1161/JAHA.119.013933Scopus ID
2-s2.0-85078888113 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
Khalaf FK, Tassavvor I, Mohamed A, Chen Y, Malhotra D, Xie Z, Tian J, Haller ST, Westfall K, Tang WHW, Kennedy DJAuthor
Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBufanolides
Cardiotonic Agents
Cell Adhesion
Cell Movement
Coculture Techniques
Endothelial Cells
Epithelial Cells
Humans
Kidney Tubules, Proximal
LLC-PK1 Cells
Macrophages, Peritoneal
Mice, Knockout
Rats, Inbred Dahl
Signal Transduction
Sodium-Potassium-Exchanging ATPase
Swine
src-Family Kinases
