Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 9, Issue 3, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.119.013933
Keywords
adhesion; cardiotonic steroids; macrophage; Na+; K+-ATP ase; renal epithelium; renal inflammation
Categories
Funding
- National Institutes of Health [HL-137004, HL-105649]
- National Affiliate of the American Heart Association [14SDG18650010, 17SDG33661117]
- American Society of Nephrology
- David and Helen Boone Foundation Research Fund
- Central Society for Clinical and Translational Research
- University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center
- University of Toledo Medical Research Society
- Cleveland Clinic Research Program Committees grant award
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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 alpha-1 (NKA alpha-1) enhances immune cell recruitment and adhesion to renal epithelium that ultimately advance renal inflammation. Methods and Results We demonstrate that knockdown of the alpha-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 alpha-1 in either macrophages or renal epithelial cells as well after inhibition of NKA alpha-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 alpha-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 alpha-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.
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