Liu Jing, Jiang Chun-Ming, Feng Yuan, Zhu Wei, Jin Bo, Xia Yang-Yang, Zhang Qing-Yan, Xu Peng-Fei, Zhang Miao
Institute of Nephrology, Affiliated Drum Tower Hospital, Medical School of Nanjing University Nanjing 210008, Jiangsu Province, China.
Am J Transl Res. 2019 Mar 15;11(3):1473-1485. eCollection 2019.
Peritoneal fibrosis (PF) is characterized by progressive accumulation of extracellular matrix (ECM) components in the peritoneum under high glucose conditions. Rapamycin has previously been shown to inhibit ECM accumulation of peritoneal mesothelial cells (PMCs) and prevent PF. Here we explored the undefined mechanisms by which rapamycin inhibits ECM accumulation of PMCs. We used high-glucose peritoneal dialysis solution (PDS) in a mouse peritoneal dialysis model to induce PF and in human PMCs to stimulate ECM accumulation. The mice that received chronic PDS infusions showed typical features of PF, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and higher expressions of α-smooth muscle actin and collagen I. Rapamycin significantly ameliorated these pathological changes. There was a parallel decrease in lipid accumulation in the peritoneum of rapamycin-treated mice. Rapamycin significantly inhibited high-glucose PDS-induced ECM accumulation and reduced the lipid droplet in human PMCs in the presence of PDS. The effects of rapamycin on intracellular lipid metabolism correlated with a series of steps in lipid homeostasis; namely, a decrease in low density lipoprotein receptor-mediated lipid influx, which was mediated through the downregulation of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP cleavage-activating protein (SCAP), and an increase in adenosine triphosphate-binding cassette transporter A1-mediated lipid efflux, which was mediated through the upregulation of the liver X receptor α and peroxisome proliferator-activated receptor α. We conclude that rapamycin shows a clear protective effect on high-glucose PDS-induced PF by improving the disruption of intracellular lipid homeostasis.
腹膜纤维化（PF）的特征是在高糖条件下，腹膜中细胞外基质（ECM）成分进行性积聚。先前已证明雷帕霉素可抑制腹膜间皮细胞（PMC）的ECM积聚并预防PF。在此，我们探究了雷帕霉素抑制PMC的ECM积聚的未知机制。我们在小鼠腹膜透析模型中使用高糖腹膜透析液（PDS）诱导PF，并在人PMC中刺激ECM积聚。接受慢性PDS输注的小鼠表现出PF的典型特征，包括腹膜厚度明显增加、基质过度沉积、腹膜通透性增加以及α-平滑肌肌动蛋白和I型胶原表达升高。雷帕霉素显著改善了这些病理变化。雷帕霉素治疗的小鼠腹膜中的脂质积聚也相应减少。在存在PDS的情况下，雷帕霉素显著抑制高糖PDS诱导的ECM积聚，并减少人PMC中的脂滴。雷帕霉素对细胞内脂质代谢的影响与脂质稳态的一系列步骤相关；即低密度脂蛋白受体介导的脂质内流减少，这是通过下调固醇调节元件结合蛋白-2（SREBP-2）和SREBP裂解激活蛋白（SCAP）介导的，以及三磷酸腺苷结合盒转运体A1介导的脂质外流增加，这是通过上调肝脏X受体α和过氧化物酶体增殖物激活受体α介导的。我们得出结论，雷帕霉素通过改善细胞内脂质稳态的破坏，对高糖PDS诱导的PF显示出明显的保护作用。
