Sitter T, Haslinger B, Mandl S, Fricke H, Held E, Sellmayer A
Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians-Universität, Munich, Germany.
J Am Soc Nephrol. 1998 Nov;9(11):2005-12. doi: 10.1681/ASN.V9112005.
Peritoneal mesothelial cells are considered the predominant source of peritoneal prostanoid formation because they represent the largest resident cell population in the peritoneal cavity. The present study was designed to evaluate the effect of D-glucose, which is widely used in commercially available peritoneal dialysis fluids as an osmotic compound, on the synthesis of prostaglandins in cultured human mesothelial cells (HMC). Analysis of eicosanoid synthesis in HMC by reversed-phase HPLC revealed that 6-keto-PGF1alpha, the spontaneous hydrolysis product of prostacyclin (PGI2), and prostaglandin E2 (PGE2) were the main eicosanoids produced. Addition of D-glucose resulted in a time- and concentration-dependent (30 to 120 mM) increase in PGE2 production in HMC (24 h, 90 mM: 3.9+/-0.5 ng/10(5) cells versus 2.3+/-0.3 in untreated cells; P < 0.05). Mannitol (90 mM) or L-glucose (90 mM). nonmetabolizable osmotic compounds, also led to a significant (P < 0.05) but less intense increase in PGE2 synthesis (3.3+/-0.4 and 3.2+/-0.5 ng/10(5) cells, respectively). Increased PGE2 synthesis was completely blunted by coincubation with the specific protein kinase C (PKC) inhibitor Ro 31-8220 or downregulation of PKC activity by preincubation with phorbol myristate acetate for 16 h. Furthermore, coincubation with PD 98059, an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, also inhibited increased PGE2 synthesis by D-glucose or mannitol. In contrast, the iso-osmolar glucose polymer icodextrin, which is used as an alternative to D-glucose in peritoneal dialysis solutions, had no effect on PGE2 synthesis. These data indicate that D-glucose and metabolically inert sugars increase PGE2 synthesis in HMC at least in part by hyperosmolarity and that this effect requires activation of PKC and the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway of intracellular signaling.
腹膜间皮细胞被认为是腹膜前列腺素形成的主要来源，因为它们是腹膜腔中数量最多的常驻细胞群。本研究旨在评估D-葡萄糖（作为渗透化合物广泛用于市售腹膜透析液）对培养的人腹膜间皮细胞（HMC）中前列腺素合成的影响。通过反相高效液相色谱分析HMC中的类花生酸合成，结果显示，前列环素（PGI2）的自发水解产物6-酮-PGF1α和前列腺素E2（PGE2）是产生的主要类花生酸。添加D-葡萄糖导致HMC中PGE2产量呈时间和浓度依赖性（30至120 mM）增加（24小时，90 mM：3.9±0.5 ng/10(5)细胞，而未处理细胞为2.3±0.3；P < 0.05）。甘露醇（90 mM）或L-葡萄糖（90 mM），即不可代谢的渗透化合物，也导致PGE2合成显著增加（P < 0.05），但增幅较小（分别为3.3±0.4和3.2±0.5 ng/10(5)细胞）。与特异性蛋白激酶C（PKC）抑制剂Ro 31-8220共同孵育或用佛波醇肉豆蔻酸酯乙酸盐预孵育16小时下调PKC活性，可完全抑制PGE2合成增加。此外，与丝裂原活化蛋白激酶/细胞外信号调节激酶途径的抑制剂PD 98059共同孵育，也可抑制D-葡萄糖或甘露醇引起的PGE2合成增加。相比之下，在腹膜透析液中用作D-葡萄糖替代品的等渗葡萄糖聚合物艾考糊精对PGE2合成无影响。这些数据表明，D-葡萄糖和代谢惰性糖至少部分通过高渗作用增加HMC中PGE2的合成，并且这种作用需要激活PKC以及细胞内信号传导的丝裂原活化蛋白激酶/细胞外信号调节激酶途径。
