圣草次苷通过调节双特异性磷酸酶14（DUSP14）介导的核因子E2相关因子2（Nrf2）和核因子κB（NF-κB）信号通路减轻急性肾损伤大鼠缺血再灌注诱导的氧化应激和炎症反应。

Eriocitrin attenuates ischemia reperfusion-induced oxidative stress and inflammation in rats with acute kidney injury by regulating the dual-specificity phosphatase 14 (DUSP14)-mediated Nrf2 and nuclear factor-κB (NF-κB) pathways.

作者信息

Xu Jun, Ma Liang, Fu Ping

机构信息

Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China.

Division of Nephrology, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, China.

出版信息

Ann Transl Med. 2021 Feb;9(4):350. doi: 10.21037/atm-21-337.

BACKGROUND

Ischemia reperfusion (IR)-induced acute kidney injury (AKI) is accompanied by increased inflammatory response and oxidative stress. Eriocitrin is a flavonoid that is mainly derived from lemon or citrate juice. It exhibits various pharmacological effects and is known to have antioxidant and anti-steatotic benefits. However, research on the effect of eriocitrin against IR-induced oxidative stress and inflammation in AKI is limited.

METHODS

In this study, an OGD/R of HK-2 cell and rat model of AKI were constructed. Then the cell or rats were treated with eriocitrin at different doses (60, 30, 10 mg/kg). The levels of apoptotic were detected by flow cytometry. Inflammatory and oxidative stress factors in supernatant and tissue . Meanwhile, Western blot was used to detect the change of dual-specificity phosphatase 14 (DUSP14), Nrf2 and nuclear factor-κB (NF-κB).

RESULTS

Eriocitrin attenuated apoptosis of the human renal tubular epithelial cell line HK-2 mediated by oxygen glucose deprivation/reperfusion via the repression of inflammation and oxidative stress in a dose-dependent manner. Eriocitrin also enhanced the levels of dual-specificity phosphatase 14 (DUSP14) and Nrf2, and decreased NF-κB phosphorylation. Furthermore, the experiments indicated that eriocitrin dose-dependently alleviated IR-induced AKI and apoptosis in rats. By elevating DUSP14, eriocitrin promoted the expression of Nrf2 and inactivated NF-κB, thereby downregulating inflammation and oxidative stress. Moreover, inhibiting DUSP14 expression with protein tyrosine phosphatase (PTP) inhibitor IV reversed the kidney-protective effects of Eriocitrin.

CONCLUSIONS

Eriocitrin protected IR-induced AKI by attenuating oxidative stress and inflammation via elevating DUSP14, thereby providing a theoretical basis for the treatment of IR-induced AKI.

背景

缺血再灌注（IR）诱导的急性肾损伤（AKI）伴有炎症反应增加和氧化应激。圣草枸橼苷是一种主要来源于柠檬或柠檬汁的黄酮类化合物。它具有多种药理作用，已知具有抗氧化和抗脂肪变性的益处。然而，关于圣草枸橼苷对IR诱导的AKI中氧化应激和炎症的影响的研究有限。

方法

在本研究中，构建了HK-2细胞的氧糖剥夺/再灌注（OGD/R）模型和AKI大鼠模型。然后用不同剂量（60、30、10mg/kg）的圣草枸橼苷处理细胞或大鼠。通过流式细胞术检测凋亡水平。检测上清液和组织中的炎症和氧化应激因子。同时，使用蛋白质免疫印迹法检测双特异性磷酸酶14（DUSP14）、核因子E2相关因子2（Nrf2）和核因子κB（NF-κB）的变化。

结果

圣草枸橼苷通过抑制炎症和氧化应激，以剂量依赖的方式减轻了氧糖剥夺/再灌注介导的人肾小管上皮细胞系HK-2的凋亡。圣草枸橼苷还提高了双特异性磷酸酶14（DUSP14）和Nrf2的水平，并降低了NF-κB磷酸化。此外，体内实验表明圣草枸橼苷剂量依赖性地减轻了IR诱导的大鼠AKI和凋亡。通过升高DUSP14，圣草枸橼苷促进了Nrf2的表达并使NF-κB失活，从而下调炎症和氧化应激。此外，用蛋白酪氨酸磷酸酶（PTP）抑制剂IV抑制DUSP14表达可逆转圣草枸橼苷的肾脏保护作用。