Abstract
BackgroundRecent studies have indicated that microRNA-223 (miR-223) plays a role in the tissue-protective effect of mesenchymal stem cells (MSCs). NLR family-pyrin domain containing 3 (NLRP3) was reported to affect a renal ischemia/reperfusion (I/R) injury by exerting a direct effect on the renal tubular epithelium. Therefore, we investigated how miR-223 and NLRP3 might function in kidneys exposed to conditions of ischemia and subsequent reperfusion.MethodsHypoxia/reoxygenation (H/R) murine renal tubular epithelial cells (RTECs) were cocultured with either MSCs or hypoxia-pretreated MSCs (htMSCs), after which the RTECs were examined for their viability and evidence of apoptosis. Next, miR-223 expression in the MSCs was downregulated to verify that MSCs protected RTECs via the transport of miR-223. Kidney I/R KM/NIH mouse models were created and used for in vivo studies.ResultsThe results showed that coculture with MSCs significantly increased the viability of RTECs and decreased their rates of apoptosis. The levels of hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF) in samples of coculture supernatants were higher than those in samples of non-coculture supernatants. A bioinformatics analysis revealed a targeting relationship between miR-223 and NLRP3. A dual luciferase assay showed that miR-223 inhibited NLRP3 expression. The htMSCs displayed a protective function associated with an upregulation of miR-223 as induced by Notch1 and the downregulation of NLRP3. Conversely, inhibition of miR-223 impeded the protective effect of MSCs. In the I/R mouse models, injection of either MSCs or htMSCs ameliorated the damage to kidney tissue, while suppression of miR-223 expression in MSCs reduced their protective effect on mouse kidneys.ConclusionsOur results demonstrate that miR-223 and NLRP3 play important roles in the treatment of renal tissue injuries with transplanted MSCs.
Highlights
Recent studies have indicated that microRNA-223 plays a role in the tissue-protective effect of mesenchymal stem cells (MSCs)
When examined at 72 h, the difference in optical density (OD450) values between H/R Renal tubular epithelial cell (RTEC) that were cocultured with MSCs and H/R RTECs that were not cocultured with MSCs was statistically significant (P < 0.05; Fig. 1a)
The cellular activity of RTECs treated with Hypoxia-pretreated mesenchymal stem cell (htMSC) at 72 h was higher than that of RTECs treated with normal MSCs
Summary
Recent studies have indicated that microRNA-223 (miR-223) plays a role in the tissue-protective effect of mesenchymal stem cells (MSCs). We investigated how miR-223 and NLRP3 might function in kidneys exposed to conditions of ischemia and subsequent reperfusion. The re-initiation of blood flow to ischemic kidney regions restores their function, the restoration process itself can further damage kidney tissue, resulting in an ischemia/reperfusion (I/R) injury [5]. Considerable effort has being made to improve the treatment of renal I/R injuries, and a variety of agents and growth factors have been proven effective for treating these disorders. Most of these treatment modalities were validated in animal models, and no significant efficacy was demonstrated in human clinical trials [6]. The development of novel and effective strategies for managing and treating renal I/R injuries remains a high priority
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