Propofol attenuates sepsis-induced acute kidney injury by regulating miR-290-5p/CCL-2 signaling pathway

Previous studies have indicated that propofol has immunomodulatory and antioxidative properties. However, the renoprotection effect and the precise mechanisms of propofol in sepsis-induced renal injury remain unclear. The purpose of the present study was to investigate the role of miR-290-5p/CCL-2 signaling in septic mice treatment with propofol. Mice were treated with propofol (50 mg/kg) twice within 24 h. Survival outcome was monitored within 48 h. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Mouse podocytes (MPC5) were treated with lipopolysaccharide (LPS) to establish the cell model in vitro. The proliferation of MPC5 was monitored using the MTS assay. Cell apoptosis was analyzed by flow cytometry. Propofol improved survival outcome and alleviated acute kidney injury in cecal ligation and puncture-operated mice. Propofol increased miR-290-5p expression and decreased CCL-2 and inflammatory cytokines levels in the kidney for septic mice. We found that miR-290-5p was a direct regulator of CCL-2 in MPC5. Propofol could abrogate LPS-induced growth inhibition and apoptosis in MPC5. Meanwhile, propofol inhibited CCL-2 expression in LPS-treated MPC5, however, knockdown of miR-290-5p abrogated the inhibitory effect propofol on the mRNA and protein expressions of CCL-2. Propofol could serve as an effective therapeutic medication to suppress sepsis-induced renal injury in vivo and in vitro by regulating the miR-290-5p/CCL-2 signaling pathway.

既往研究表明，丙泊酚（propofol）具备免疫调节与抗氧化特性。然而，丙泊酚在脓毒症诱导肾损伤中的肾脏保护作用及其确切分子机制仍未明确。本研究旨在探讨miR-290-5p/CCL-2信号通路在丙泊酚治疗脓毒症小鼠中的作用。实验中，小鼠于24小时内两次给予丙泊酚（50 mg/kg），并于48小时内监测其生存结局。分别采用实时荧光定量聚合酶链反应（qRT-PCR）与蛋白质印迹法（western blotting）检测mRNA与蛋白的表达水平。采用脂多糖（lipopolysaccharide, LPS）处理小鼠足细胞（MPC5）以构建体外细胞模型，通过MTS法检测MPC5细胞的增殖能力，利用流式细胞术分析细胞凋亡情况。结果显示，丙泊酚可改善盲肠结扎穿刺术（cecal ligation and puncture, CLP）致脓毒症小鼠的生存结局，并减轻其急性肾损伤；丙泊酚可上调脓毒症小鼠肾脏组织中miR-290-5p的表达，同时下调CCL-2与炎性细胞因子的水平。本研究证实，miR-290-5p可直接调控MPC5细胞中CCL-2的表达；丙泊酚可逆转LPS诱导的MPC5细胞增殖抑制与凋亡，同时抑制LPS处理的MPC5细胞中CCL-2的表达，但敲低miR-290-5p可抵消丙泊酚对CCL-2 mRNA及蛋白表达的抑制作用。综上，丙泊酚可通过调控miR-290-5p/CCL-2信号通路，在体内外均发挥抑制脓毒症诱导肾损伤的有效治疗作用。