Ito Takafumi, Yorioka Noriaki, Yamamoto Masao, Kataoka Katsuko, Yamakido Michio
Department of Internal Medicine II, Hiroshima University School of Medicine, Hiroshima, Japan.
Department of Anatomy II, Hiroshima University School of Medicine, Hiroshima, Japan.
J Am Soc Nephrol. 2000 Nov;11(11):1969-1979. doi: 10.1681/ASN.V11111969.
During continuous ambulatory peritoneal dialysis, the peritoneum is directly and continuously exposed to unphysiologic peritoneal dialysis fluid; the resulting mesothelial damage has been suggested to cause loss of ultrafiltration and dialysis efficacy. The present study investigated the effect of a high glucose concentration on cultured human peritoneal mesothelial cells to clarify the cause of decreased dialysis efficacy during prolonged peritoneal dialysis. High glucose caused a concentration-dependent decrease in cell proliferation, damage to the intercellular junctions, and excess production of transforming growth factor-beta (TGF-beta). The levels of intercellular junctional proteins (ZO-1, E-cadherin, and beta-catenin) were decreased, and immuno-staining by anti-ZO-1 and anti- beta-catenin antibodies became weaker and often discontinuous along the cell contour. Mannitol had similar but weaker effects at the same osmolality, and an anti-TGF-beta neutralizing antibody reduced the effects of high glucose. Therefore, these effects were induced not only by glucose itself but also by hyperosmolality and by a glucose-induced increase of TGF-beta. These findings suggest that the peritoneal mesothelium is damaged by prolonged peritoneal dialysis using high glucose dialysate and that impairment of the intercellular junctions of peritoneal mesothelial cells by high glucose dialysate induces peritoneal hyperpermeability and a progressive reduction in dialysis efficacy.
在持续性非卧床腹膜透析期间，腹膜直接且持续暴露于非生理性腹膜透析液中；由此产生的间皮损伤被认为会导致超滤功能丧失和透析效果下降。本研究调查了高糖浓度对培养的人腹膜间皮细胞的影响，以阐明长期腹膜透析期间透析效果降低的原因。高糖导致细胞增殖呈浓度依赖性下降、细胞间连接受损以及转化生长因子-β（TGF-β）过度产生。细胞间连接蛋白（ZO-1、E-钙黏蛋白和β-连环蛋白）水平降低，抗ZO-1和抗β-连环蛋白抗体的免疫染色沿细胞轮廓变弱且常不连续。在相同渗透压下，甘露醇有类似但较弱的作用，抗TGF-β中和抗体可减轻高糖的作用。因此，这些作用不仅由葡萄糖本身诱导，还由高渗以及葡萄糖诱导的TGF-β增加所诱导。这些发现表明，使用高糖透析液进行长期腹膜透析会损害腹膜间皮，并且高糖透析液对腹膜间皮细胞间连接的损害会导致腹膜高通透性和透析效果逐渐降低。
