Abstract：
OBJECTIVE: As one of the most serious complications of sepsis, acute kidney injury (AKI) is pathologically associated with excessive inflammation. 2,5-Dihydroxyacetophenone (DHAP) is isolated from Radix rehmanniae praeparata and exhibit potent anti-inflammatory property. This research aimed at determining the role of DHAP in sepsis-associated AKI (SA-AKI) and the underlying mechanism.
METHODS: Plasma creatinine (Cre), blood urea nitrogen (BUN), tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels of SA-AKI patients were detected to evaluate their clinical characteristics. SA-AKI rat models were established by using caecum ligation puncture (CLP) surgery. CLP-induced rats were administered via oral gavage with 20 or 40 mg DHAP after 2 h of CLP surgery. Subsequently, survival rates, serum indexes, histopathological changes, inflammatory factors, renal function indexes and extracellular regulated protein kinases (ERK) and nuclear factor-κB (NF-κB) signalling pathways were detected.
RESULTS: SA-AKI patients exhibited markedly higher levels of plasma Cre, BUN, TNF-α and IL-1β than healthy people. Compared with sham rats, CLP-induced septic rats showed significantly decreased survival rate, increased serum lactate dehydrogenase activity and serum lactate level, obvious renal histopathological injury, upregulated TNF-α, IL-1β and TGF-β1 levels, elevated serum creatinine, BUN and serum cystatin C concentrations, serum neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels and reduced renal artery blood flow. All the above CLP-induced changes in septic rats were mitigated after DHAP administration. Additionally, CLP-induced elevation in phosphorylated-ERK1/2 and nuclear NF-κB p65 protein levels was inhibited by DHAP treatment.
CONCLUSIONS: DHAP hinders SA-AKI progression in rat models by inhibiting ERK and NF-κB signalling pathways.
METHODS: Plasma creatinine (Cre), blood urea nitrogen (BUN), tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels of SA-AKI patients were detected to evaluate their clinical characteristics. SA-AKI rat models were established by using caecum ligation puncture (CLP) surgery. CLP-induced rats were administered via oral gavage with 20 or 40 mg DHAP after 2 h of CLP surgery. Subsequently, survival rates, serum indexes, histopathological changes, inflammatory factors, renal function indexes and extracellular regulated protein kinases (ERK) and nuclear factor-κB (NF-κB) signalling pathways were detected.
RESULTS: SA-AKI patients exhibited markedly higher levels of plasma Cre, BUN, TNF-α and IL-1β than healthy people. Compared with sham rats, CLP-induced septic rats showed significantly decreased survival rate, increased serum lactate dehydrogenase activity and serum lactate level, obvious renal histopathological injury, upregulated TNF-α, IL-1β and TGF-β1 levels, elevated serum creatinine, BUN and serum cystatin C concentrations, serum neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels and reduced renal artery blood flow. All the above CLP-induced changes in septic rats were mitigated after DHAP administration. Additionally, CLP-induced elevation in phosphorylated-ERK1/2 and nuclear NF-κB p65 protein levels was inhibited by DHAP treatment.
CONCLUSIONS: DHAP hinders SA-AKI progression in rat models by inhibiting ERK and NF-κB signalling pathways.
摘要：
目的：作为脓毒症最严重的并发症之一，急性肾损伤（AKI）在病理上与过度炎症有关。2,5-二羟基苯乙酮(DHAP)分离自熟地黄并表现出有效的抗炎性质。本研究旨在确定DHAP在脓毒症相关AKI（SA-AKI）中的作用及其潜在机制。
方法：血浆肌酐（Cre），血尿素氮(BUN),检测SA-AKI患者的肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平，以评估其临床特征。采用盲肠结扎穿刺(CLP)手术建立SA-AKI大鼠模型。CLP诱导的大鼠在CLP手术2小时后通过口服灌胃给予20或40mgDHAP。随后，存活率,血清指标，组织病理学变化,炎症因子，检测肾功能指标和细胞外调节蛋白激酶（ERK）和核因子-κB（NF-κB）信号通路。
结果：SA-AKI患者血浆Cre水平明显升高，BUN,TNF-α和IL-1β高于健康人。与假大鼠相比，CLP诱导的脓毒症大鼠存活率明显降低，增加血清乳酸脱氢酶活性和血清乳酸水平，明显的肾组织病理学损伤，上调TNF-α，IL-1β和TGF-β1水平，血清肌酐升高,BUN和血清胱抑素C浓度，血清中性粒细胞明胶酶相关脂质运载蛋白和肾损伤分子-1水平和肾动脉血流量减少。给予DHAP后，所有上述CLP诱导的脓毒症大鼠的变化均得到缓解。此外,DHAP处理抑制了CLP诱导的磷酸化ERK1/2和核NF-κBp65蛋白水平的升高。
结论：DHAP通过抑制ERK和NF-κB信号通路来阻碍大鼠模型中SA-AKI的进展。
方法：血浆肌酐（Cre），血尿素氮(BUN),检测SA-AKI患者的肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平，以评估其临床特征。采用盲肠结扎穿刺(CLP)手术建立SA-AKI大鼠模型。CLP诱导的大鼠在CLP手术2小时后通过口服灌胃给予20或40mgDHAP。随后，存活率,血清指标，组织病理学变化,炎症因子，检测肾功能指标和细胞外调节蛋白激酶（ERK）和核因子-κB（NF-κB）信号通路。
结果：SA-AKI患者血浆Cre水平明显升高，BUN,TNF-α和IL-1β高于健康人。与假大鼠相比，CLP诱导的脓毒症大鼠存活率明显降低，增加血清乳酸脱氢酶活性和血清乳酸水平，明显的肾组织病理学损伤，上调TNF-α，IL-1β和TGF-β1水平，血清肌酐升高,BUN和血清胱抑素C浓度，血清中性粒细胞明胶酶相关脂质运载蛋白和肾损伤分子-1水平和肾动脉血流量减少。给予DHAP后，所有上述CLP诱导的脓毒症大鼠的变化均得到缓解。此外,DHAP处理抑制了CLP诱导的磷酸化ERK1/2和核NF-κBp65蛋白水平的升高。
结论：DHAP通过抑制ERK和NF-κB信号通路来阻碍大鼠模型中SA-AKI的进展。
