Moreira Roberto S, Irigoyen Maria, Sanches Talita R, Volpini Rildo A, Camara Niels O S, Malheiros Denise M, Shimizu Maria H M, Seguro Antonio C, Andrade Lucia
Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil; Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil;
Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil;
Am J Physiol Regul Integr Comp Physiol. 2014 Sep 1;307(5):R514-24. doi: 10.1152/ajpregu.00445.2013. Epub 2014 Jun 11.
Kidney injury, heart injury, and cytokine-induced vascular hyperpermeability are associated with high rates of morbidity and mortality in sepsis. Although the mechanism remains unknown, apolipoprotein A-I (apoA-I) mimetic peptide 4F reduces inflammation and protects HDL levels, which are reduced in sepsis. We hypothesized that 4F also protects kidneys and hearts in a rat model of cecal ligation and puncture (CLP). We divided Wistar rats into groups: sham-operated (control), CLP, and CLP+4F (10 mg/kg body wt ip, 6 h after CLP). At 24 h post-CLP, we evaluated cardiac function, mean arterial pressure (MAP), heart rate (HR), baroreflex sensitivity, total cholesterol, LDL, HDL, serum cytokines, and inulin clearance. We performed immunoblotting for protein regulators of vascular permeability (Slit2 and Robo4) and endothelial nitric oxide synthase (eNOS) in kidney tissue. We evaluated heart mitochondria with electron microscopy. Although there was no difference in MAP, the HR was significantly higher in CLP rats than in control and CLP+4F rats. In CLP+4F rats, baroreflex sensitivity and cardiac function were completely protected from the effects of CLP, as was glomerular filtration; heart mitochondria morphology was improved; sepsis-induced changes in serum cholesterol, LDL, HDL, and apoA-I were less common; all cytokines were lower than in CLP rats; and expression of Slit2, Robo4, and eNOS was completely restored. Administration of 4F inhibits inflammatory responses and strengthens the vascular barrier, protecting kidneys and hearts in an HDL-dependent manner. To determine the extent of the protective effect of 4F, further studies are needed.
肾损伤、心脏损伤以及细胞因子诱导的血管通透性增加与脓毒症的高发病率和死亡率相关。尽管其机制尚不清楚，但载脂蛋白A-I（apoA-I）模拟肽4F可减轻炎症并保护高密度脂蛋白（HDL）水平，而HDL水平在脓毒症中会降低。我们推测4F在盲肠结扎和穿刺（CLP）大鼠模型中也能保护肾脏和心脏。我们将Wistar大鼠分为几组：假手术组（对照组）、CLP组和CLP + 4F组（CLP术后6小时腹腔注射10 mg/kg体重）。在CLP术后24小时，我们评估了心脏功能、平均动脉压（MAP）、心率（HR）、压力反射敏感性、总胆固醇、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、血清细胞因子以及菊粉清除率。我们对肾组织中血管通透性的蛋白调节因子（Slit2和Robo4）以及内皮型一氧化氮合酶（eNOS）进行了免疫印迹分析。我们用电子显微镜评估了心脏线粒体。尽管MAP没有差异，但CLP大鼠的HR显著高于对照组和CLP + 4F大鼠。在CLP + 4F大鼠中，压力反射敏感性和心脏功能完全免受CLP的影响，肾小球滤过功能也是如此；心脏线粒体形态得到改善；脓毒症诱导的血清胆固醇、LDL、HDL和apoA-I变化较少见；所有细胞因子均低于CLP大鼠；Slit2、Robo4和eNOS的表达完全恢复。给予4F可抑制炎症反应并加强血管屏障，以HDL依赖的方式保护肾脏和心脏。为了确定4F的保护作用程度，还需要进一步研究。
