J Biomed Nanotechnol. 2021 Jan 1;17(1):64-77. doi: 10.1166/jbn.2021.3010.
Apigenin as a natural flavonoid product has been proved previously to play a renoprotective effect during ischemia/reperfusion injury (IRI), but the particular mechanisms involving the positive effects of apigenin remain totally unclear. The study investigated apigenin's roles and underlying biological mechanisms in IR-induced acute kidney injury (AKI). Thirty-six mice received a right nephrectomy and clamping of the left renal artery for 30 minutes, and then perfusion for 24 h. Apigenin was loaded onto a biodegradable polymer carrier (nanoparticle) to enhance its bioavailability. Mice were subjected to intraperitoneally injection with apigenin (5, 10 or 20 mg/kg) for 24 h before surgery. For experiments, mouse renal tubular epithelial cells (mRTECs) and miR-140-5p mimic/inhibitor transfected mRTECs were subjected to hypoxia/reoxygenation in the presence or absence of apigenin. , we uncovered that hypoxia/reoxygenation stimulation caused inflammatory injury in mRTECs. Apigenin reduced the hypoxia/reoxygenation-induced cell inflammatory injury and NF- B p65 nuclear translocation from cytoplasm and activation. Moreover, apigenin reduced hypoxia/reoxygenationtriggered miR-140-5p down-regulation. What's more, the luciferase reporter system revealed that miR-140-5p negatively regulates CXCL12, which is its direct target of action. CXCL12 exhibited an inhibitory effect on the apigenin-induced inactivation of NF- B signaling pathway. Furthermore, we observed that apigenin pretreatment attenuated the IR-triggered up-regulation of serum creatinine and blood urea nitrogen, elevation of pro-inflammatory cytokines secretion and tubular cell apoptosis, enhancement of CXCL12 and decline of miR-140-5p . Our studies show that apigenin protects against IR-triggered renal cell inflammatory injury and by miR-140-5p up-regulation and CXCL12 downregulation via quenching the NF- B pathway activation. Apigenin may be an encouraging therapeutic agent for patients with IR-associated kidney injury.
柚皮素作为一种天然类黄酮产物，先前已被证明在缺血/再灌注损伤（IRI）中具有肾保护作用，但柚皮素发挥积极作用的特定机制尚完全不清楚。本研究探讨了柚皮素在IRI 引起的急性肾损伤（AKI）中的作用和潜在生物学机制。36 只小鼠接受右肾切除术和左肾动脉夹闭 30 分钟，然后再灌注 24 小时。柚皮素被加载到可生物降解的聚合物载体（纳米颗粒）上，以提高其生物利用度。手术前 24 小时，小鼠通过腹腔内注射柚皮素（5、10 或 20mg/kg）。对于实验，在存在或不存在柚皮素的情况下，将小鼠肾小管上皮细胞（mRTECs）和 miR-140-5p 模拟物/抑制剂转染的 mRTECs 进行缺氧/复氧处理。结果表明，缺氧/复氧刺激导致 mRTECs 发生炎症损伤。柚皮素降低了缺氧/复氧诱导的细胞炎症损伤和 NF- B p65 从细胞质和激活中的核易位。此外，柚皮素降低了缺氧/复氧触发的 miR-140-5p 下调。更重要的是，荧光素酶报告系统显示，miR-140-5p 负调控 CXCL12，是其直接作用靶点。CXCL12 对柚皮素诱导的 NF- B 信号通路失活具有抑制作用。此外，我们观察到，柚皮素预处理可减轻 IR 触发的血清肌酐和血尿素氮升高、促炎细胞因子分泌增加和肾小管细胞凋亡、CXCL12 增强和 miR-140-5p 下调。我们的研究表明，柚皮素通过 miR-140-5p 上调和 CXCL12 下调来抑制 NF- B 通路激活，从而防止 IR 触发的肾细胞炎症损伤。柚皮素可能是治疗与 IR 相关的肾损伤患者的一种有希望的治疗剂。
