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Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Front+Physiol 2018 ; 9 (ä): ä Nephropedia Template TP
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Eplerenone Reverses Cardiac Fibrosis via the Suppression of Tregs by Inhibition of Kv1 3 Channel #MMPMID30057554
Shao PP; Liu CJ; Xu Q; Zhang B; Li SH; Wu Y; Sun Z; Cheng LF
Front Physiol 2018[]; 9 (ä): ä PMID30057554show ga
Background: Fibroblast proliferation is a critical feature during heart failure development. Previous studies reported regulatory T-lymphocytes (Tregs)? protective role against myocardial fibrosis. However, notably, Tregs also secrete fibrogenic cytokine TGF-? when activated. This study aimed to clarify the intriguing link between Tregs and fibrosis, the role of Tregs Kv1.3 potassium channel (regulating T-lymphocytes activation) in the fibrosis process, and how selective aldosterone receptor antagonist Eplerenone affects Tregs and fibrosis through its action on Kv1.3 channel.Methods and Results: After co-incubation with Tregs, cardiac fibroblast proliferation (CCK-8 assay) and levels of collagen I, III, and Matrix metalloproteinase2 (ELISA) significantly elevated. Cell viability assays, Kv1.3 channel mRNA (RT-qPCR), and protein expression (In-Cell Western Blotting) revealed Tregs were activated/proliferated when co-cultured with fibroblasts. Treg intracellular TGF-? level increased by 5.8-fold, far more than that of intracellular IL-10, extracellular TGF-? and IL-10 (ELISA). And 30 ?M eplerenone suppressed Tregs proliferation by 82.77% and furthermore, suppressed intracellular TGF-? level to a significantly greater extent than that of intracellular IL-10, extracellular TGF-? and IL-10. Moreover, the Kv1.3 current (whole-cell patch clamp) of Tregs in congestive heart failure patients and rats (induced by coronary artery ligation and exhaustive exercise) elevated by >4-fold than that of healthy volunteers and control rats, whereas 30 ?M eplerenone suppressed the current by >60% in control Tregs. In addition, docking calculations (AutoDock software 4.0 suite) showed eplerenone has higher H-bond energy with Kv1.3 channel than other selective blockers.Conclusion: Immuno-regulation in the late stage of CHF activates Tregs proliferation via the upregulation of Kv1.3 channels, which promotes cardiac fibrosis by primarily secreting TGF-?. Taken together, eplerenone?s high affinity to Kv1.3 channel enables it to antagonize the Kv1.3 channels directly to suppress Tregs proliferation, which in turn may play an immuno-regulatory role during CHF.