Abstract
BackgroundHonokiol is a low-molecular-weight natural product and has been reported to exhibit anti-inflammatory activity.ObjectivesOur study aimed to investigate the influence of honokiol on sepsis-induced acute kidney injury (AKI) in a mouse model.Material and methodsA cecal ligation and puncture (CLP) surgical operation was performed to establish a sepsis-induced acute kidney injury model in mice. Renal histomorphological analysis was performed with periodic acid-Schiff (PAS) staining. The levels of inflammatory markers in serum were measured by ELISA assay. The mRNA and protein levels were assayed by RT-qPCR and western blotting, respectively. Annexin V-FITC/PI staining was used to evaluate glomerular mesangial cell (GMC) apoptosis.ResultsThe results revealed that honokiol significantly increased the survival rate in mice undergoing a CLP operation. Inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, were significantly inhibited in honokiol-treated septic mice compared with the CLP group. In addition, honokiol showed the ability to reverse CLP-induced AKI in septic mice. Furthermore, heme oxygenase-1 (HO-1) expression levels were significantly up-regulated and miR-218-5p was markedly down-regulated in honokiol-treated septic mice as compared to CLP-operated mice. Bioinformatics and experimental measurements showed that HO-1 was a direct target of miR-218-5p. In vitro experiments showed that both honokiol and miR-218-5p inhibitors blocked lipopolysaccharide (LPS)-induced cell growth inhibition and GMC apoptosis by increasing the expression of HO-1.ConclusionsHonokiol ameliorated AKI in septic mice and LPS-induced GMC dysfunction, and the underlying mechanism was mediated, at least partially, through the regulation of miR-218-5p/HO-1 signaling.
Highlights
Sepsis is caused by infections with bacteria such as Staphylococcus aureus and is characterized by a whole-body inflammatory response, which is a leading cause of death in intensive care units (ICUs) [1]
The results demonstrated that both low-concentration and high-concentration honokiol significantly increased the survival in mice undergoing cecal ligation and puncture (CLP) as compared to mice only treated with CLP (Fig. 1)
Bacterial counts in septic mouse organs are inhibited after honokiol treatment Bacterial counts in blood, kidney, liver and brain were measured after induction of sepsis with CLP treatment for 24 h
Summary
Sepsis is caused by infections with bacteria such as Staphylococcus aureus and is characterized by a whole-body inflammatory response, which is a leading cause of death in intensive care units (ICUs) [1]. Inflammatory reaction triggered by cytokine production is a leading cause of sepsis-induced multiple organ system failure, little progress has been made in the management of sepsis. Previous studies have demonstrated that honokiol alleviates experimental mesangial proliferative glomerulonephritis [6] and inhibits LPS- and high-glucose-induced upregulation of inflammatory cytokines in human renal mesangial cells (HRMCs) [7, 8]. Honokiol protects against renal ischemia/reperfusion injury via the suppression of oxidative stress and inflammatory reactions in a rat model [10]. Honokiol ameliorates sepsis-associated acute lung injury [5] and kidney injury [11] in murine models via the inhibition of oxidative stress and inflammation. The underlying molecular mechanisms of sepsis-induced AKI and the protective effect of honokiol in sepsis-induced organ failure have not been clearly delineated. Honokiol is a low-molecular-weight natural product and has been reported to exhibit anti-inflammatory activity
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