Abstract
Purpose: To investigate the protective effect of ligustilide on sepsis-induced acute kidney injury (AKI) and the signaling pathways involved.Methods: Sepsis-induced AKI was established by cecal ligation and puncture (CLP) in mice. Histopathological renal damage was examined using hematoxylin and eosin (H & E) staining while creatinine and cytokines were measured using commercial kits. Protein levels were determined by Western blotting.Results: Vacuoles, dilations, degeneration, and necrosis were observed in CLP mouse kidneys, but these alterations were countered by 20 mg/kg of ligustilide. Serum creatinine, blood urea nitrogen (BUN), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were significantly increased in CLP mice compared with control. Furthermore, the serum levels of these indicators in serum were lowered by ligustilide (p < 0.01). The expression levels of Toll-like receptor 4 (TLR4) TLR4 and phosphorylated nuclear factor (NF)-κB in CLP mice were also downregulated by ligustilide. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels increased in CLP mice, but were attenuated by ligustilide (p < 0.01). Superoxide dismutase (SOD) and glutathione (GSH) levels decreased in CLP mice but were increased by ligustilide (p < 0.01). Increased expression of Nrf2 and heme oxygenase-1 (HO-1) were observed in CLP mice, and were further enhancced by ligustilide.Conclusion: Ligustilide exerts antioxidant and anti-inflammatory effects on sepsis-induced AKI via TLR4/NF-κB and Nrf2/HO-1 signaling pathways.
 Keywords: Ligustilide, Sepsis, Acute kidney injury, TLR4/NF-κB signaling pathway, Nrf2/HO-1 signaling pathway
Highlights
Sepsis is a systemic disorder characterized by acute organ dysfunction and high mortality [1]
Serum creatinine was higher in cecal ligation and puncture (CLP) mice than that in Sham group; this induction was attenuated by 20 mg/kg of ligustilide. (Figure 1 A)
blood urea nitrogen (BUN) level in blood serum was higher in CLP mice than that in Sham mice, which was decreased by 20 mg/kg of ligustilide (Figure 1 B)
Summary
Sepsis is a systemic disorder characterized by acute organ dysfunction and high mortality [1]. An estimated 40 – 50 % cases of acute kidney injury (AKI) are caused by sepsis, which increases the risk of death by 6- to 8-fold, Sepsis-induced AKI is highly associated with inflammatory factors (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) [5]. Oxidative stress is a crucial contributor to sepsis-induced AKI [4]. Reactive oxygen species (ROS) production is increased by bacteria and promotes apical epithelial tubular cell vacuolization, which results in the apoptosis or necrosis of tubular cells, indicating that oxidative stress is closely related to the dysfunction of tubular [4]. Suppressing inflammation and oxidative stress may prevent sepsis-induced AKI
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