Abstract 15042: Partial Nephrectomy Regulates Cardiac Tissue MicroRNA-29b-3p and Causes Cardiac Fibrosis Through a Na/K-ATPase-Src-NF-kappa B Mediated Pathway in Mice
Introduction: Cardiac fibrosis is a common pathological process in different cardio-renal diseases. We have previously reported that activation of Na/K-ATPase signaling by its ligands, cardiotonic steroids (CTS), contributes to cardiac fibrosis in animal models with CKD. Our recent study revealed that Na/K-ATPase mediated regulation of Src kinase signaling regulates collagen synthesis in cardiac fibroblasts through decreasing expression of microRNA-29b-3p (miR-29b).
Methods: To test whether the same mechanism mediates PNx-induced cardiac fibrosis in vivo, we performed the commonly used model of CKD, 5/6th partial nephrectomy (PNx) surgery on mice with a C57/BL6 background. Twelve weeks after PNx or sham surgery, these mice were injected with pNaKtide, a Src inhibiting peptide, at a dose of 25mg/kg intraperitoneally one time every other week before sacrifice was performed at the end of 16th week following surgery. Mice injected with similar volumes of saline were used as control.
Results: The experimental results showed that pNaKtide significantly reduced cardiac fibrosis (14.1±4.3% vs 1.5±0.4%, p<0.05). We further found that PNx decreased miR-29b-3p by about 2-fold in heart tissue from these mice, while pNaKtide restored miR-29b-3p expression to the level of sham-operated mice. PNx also significantly increased expression of the miR-29b-3p suppressive element NF-kappa B p65 in cardiac tissue. In isolated cardiac fibroblasts, we further demonstrated that CTS treatment activates NF-kappa B and decreases miR-29b, whereas inhibition of NF-kappa B by Bay11-7082 blocked CTS-induced decreases in miR-29b. Using cardiac fibroblast isolated from a Na/K-ATPase alpha 1 heterozygous mice, we found that genetic reduction of Na/K-ATPase alpha 1 blunted CTS-induced miR-29b dysregulation. However, the baseline Src activation is higher while the baseline miR-29b is lower in these Na/K-ATPase reduced cells.
Conclusions: These results demonstrated that Na/K-ATPase, Src, and NF-kappa B signaling contribute to PNx-induced cardiac fibrosis via regulation of miR-29b expression in heart tissue.
Author Disclosures: C.A. Drummond: None. X. Fan: None. H. Shi: None. J.X. Xie: None. S.T. Haller: None. C.J. Cooper: None. J. Tian: None.
- © 2016 by American Heart Association, Inc.