Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts

Abstract

Chronic kidney disease (CKD) is accompanied by cardiac fibrosis, hypertrophy, and dysfunction, which are commonly referred to as uremic cardiomyopathy. Our previous studies found that Na/K-ATPase ligands or 5/6th partial nephrectomy (PNx) induces cardiac fibrosis in rats and mice. The current study used in vitro and in vivo models to explore novel roles for microRNA in this mechanism of cardiac fibrosis formation. To accomplish this, we performed microRNA profiling with RT-qPCR based arrays on cardiac tissue from rats subjected to marinobufagenin (MBG) infusion or PNx. The analysis showed that a series of fibrosis-related microRNAs were dysregulated. Among the dysregulated microRNAs, microRNA (miR)-29b-3p, which directly targets mRNA of collagen, was consistently reduced in both PNx and MBG-infused animals. In vitro experiments demonstrated that treatment of primary cultures of adult rat cardiac fibroblasts with Na/K-ATPase ligands induced significant increases in the fibrosis marker, collagen protein, and mRNA expression compared with controls, whereas miR-29b-3p expression decreased >50%. Transfection of miR-29b-3p mimics into cardiac fibroblasts inhibited cardiotonic steroids-induced collagen synthesis. Moreover, a specific Na/K-ATPase signaling antagonist, pNaKtide, prevented ouabain-induced increases in collagen synthesis and decreases in miR-29b-3p expression in these cells. In conclusion, these data are the first to indicate that signaling through Na/K-ATPase regulates miRNAs and specifically, miR-29b-3p expression both in vivo and in vitro. Additionally, these data indicate that miR-29b-3p expression plays an important role in the formation of cardiac fibrosis in CKD.

Bone marrow mesenchymal stem cells reduce ureteral stricture formation in a rat model via the paracrine effect of extracellular vesicles

“…Results from the miRTarBase using specific search strategy (keywords: “Bone marrow‐derived mesenchymal stem cells,” “microRNA,” “fibrosis” and “exosome”) showed that the 24 potential miRNAs target TGF‐β1 and might play role in anti‐fibrotic. After reviewing of pertinent literatures, we identified 6 miRNAs (mir‐29b‐3p, mir‐19b‐3p, mir‐130a‐3p, mir‐590‐5p, mir‐146a‐5p and mir‐181a‐5p) were reported have the potency of anti‐fibrotic in the liver, renal, cardiac and pulmonary tissue . Therefore, we envisage the possibility that such potential cargo microRNAs in EVs may involve in the anti‐fibrotic action in US development.…”

MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes

“…Our previous study showed that miR-29b-3p as well as a set of other anti-fibrotic miRNAs were significantly decreased in cardiac tissues from rats subjected to PNx surgery [40]. The current study found that many of these anti-fibrotic miRNAs (miR-29b-3p, miR-20a-5p, and miR-19a-3p) were also decreased in the circulating exosome samples from both PNx and 2K1C animals, indicating that changes in exosomal miRNAs may reflect pathological changes in the tissue.…”

Biomarkers in patients with myocardial fibrosis

“…In chronic kidney disease (CKD), microRNA (miR)-29b-3p directly targets mRNA of collagen. Expression level of miR-29b-3p decreases in cardiac fibroblasts, which is regulated by Na/K-ATPase [36][37][38].…”