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

Fatimah K Khalaf, Iman Tassavvor, Amal Mohamed, Yiliang Chen, Deepak Malhotra, Zijian Xie, Jiang Tian, Steven T Haller, Kristen Westfall, W H Wilson Tang, David J Kennedy

Journal of the American Heart Association 2020 Feb 04

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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.

Citation

Fatimah K Khalaf, Iman Tassavvor, Amal Mohamed, Yiliang Chen, Deepak Malhotra, Zijian Xie, Jiang Tian, Steven T Haller, Kristen Westfall, W H Wilson Tang, David J Kennedy. 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. 2020 Feb 04;9(3):e013933