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Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA α-1 (Na+/K+-ATPase α-1)/Src Complex in Renal Epithelial Cells and Immune Cells
- Source :
- Hypertension
- Publication Year :
- 2019
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2019.
-
Abstract
- Cardiotonic steroids (CTSs) are NKA α-1 (Na + /K + -ATPase α-1) ligands that are increased in volume expanded states and associated with cardiac and renal diseases. Although initiation and resolution of inflammation is an important component of cellular injury and repair in renal disease, it is unknown whether CTS activation of NKA α-1 signaling in this setting regulates this inflammatory response. On this background, we hypothesized that CTS signaling through the NKA α-1–Src kinase complex promotes a proinflammatory response in renal epithelial and immune cells. First, we observed that the CTS telocinobufagin activated multiple proinflammatory cytokines/chemokines in renal epithelial cells, and these effects were attenuated after either NKA α-1 knockdown or with a specific inhibitor of the NKA α-1–Src kinase complex (pNaKtide). Similar findings were observed in immune cells, where we demonstrated that while telocinobufagin induced both oxidative burst and enhanced Nuclear factor kappa-light-chain-enhancer of activated B cells activation in macrophages ( P +/− macrophages or by pretreatment with pNaKtide or the Src inhibitor PP2 ( P +/− versus wild-type mice. Similarly, 5/6th partial nephrectomy yielded decreased levels of the urinary oxidative stress marker 8-Oxo-2′-deoxyguanosine in NKA α-1 +/− versus wild-type mice. Finally, we found that in vivo inhibition of the NKA α-1–Src kinase complex with pNaKtide significantly inhibited renal proinflammatory gene expression after 5/6th partial nephrectomy. These findings suggest that the NKA α-1–Src kinase complex plays a central role in regulating the renal inflammatory response induced by elevated CTS both in vitro and in vivo.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Chemokine
Inflammation
030204 cardiovascular system & hematology
Kidney
medicine.disease_cause
Sensitivity and Specificity
Article
Proinflammatory cytokine
Cardiac Glycosides
Mice
03 medical and health sciences
0302 clinical medicine
In vivo
Internal medicine
Internal Medicine
medicine
Animals
Renal Insufficiency, Chronic
Na+/K+-ATPase
Cells, Cultured
biology
Chemistry
Macrophages
Biopsy, Needle
Epithelial Cells
respiratory system
Immunohistochemistry
Respiratory burst
Bufanolides
030104 developmental biology
Endocrinology
biology.protein
Chemokines
Sodium-Potassium-Exchanging ATPase
medicine.symptom
Oxidative stress
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 15244563 and 0194911X
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Hypertension
- Accession number :
- edsair.doi.dedup.....c47c35d2aa3cf0e374c5d580763419db