Stoenoiu Maria S, Ni Jie, Verkaeren Charlotte, Debaix Huguette, Jonas Jean-Christophe, Lameire Norbert, Verbavatz Jean-Marc, Devuyst Olivier
Division of Nephrology and ENDO Unit, Université Catholique de Louvain Medical School, Brussels, Belgium.
J Am Soc Nephrol. 2003 Mar;14(3):555-65. doi: 10.1097/01.asn.0000053420.37216.9e.
The water channel aquaporin-1 (AQP1) is the molecular counterpart of the ultrasmall pore responsible for transcellular water permeability during peritoneal dialysis (PD). This water permeability accounts for up to 50% of ultrafiltration (UF) during a hypertonic dwell, and its loss can be a major clinical problem for PD patients. By analogy with the lung, the hypothesis was tested that corticosteroids may increase AQP1 expression in the peritoneal membrane (PM) and improve water permeability and UF in rats. First, the expression and distribution of the glucocorticoid receptor (GR) in the PM and capillary endothelium was documented. Time-course and dose-response analyses showed that a daily IM injection of dexamethasone (1 or 4 mg/kg) for 5 d induced an approximately twofold increase in the expression of AQP1 at the mRNA and protein levels. The GR antagonist RU-486 completely inhibited the dexamethasone effect. The functional counterpart of the increased AQP1 expression was a significant increase in sodium sieving and net UF across the PM, contrasting with a lack of effect on the osmotic gradient and permeability for small solutes. The latter observation reflected the lack of effect of corticosteroids on nitric oxide synthase (NOS) activity and endothelial NOS isoform expression in the PM. In conclusion, corticosteroids induce AQP1 expression in the capillary endothelium of the PM, which is reflected by increased transcellular water permeability and UF. These data emphasize the critical role of AQP1 during PD and suggest that pharmacologic regulation of AQP1 may provide a target for manipulating water permeability across the PM.
水通道蛋白-1（AQP1）是腹膜透析（PD）过程中负责跨细胞水通透性的超小孔道的分子对应物。这种水通透性在高渗驻留期间占超滤（UF）的比例高达50%，其丧失可能是PD患者的一个主要临床问题。类比于肺，我们检验了皮质类固醇可能增加大鼠腹膜（PM）中AQP1表达并改善水通透性和超滤的假说。首先，记录了糖皮质激素受体（GR）在PM和毛细血管内皮中的表达及分布。时间进程和剂量反应分析表明，每天肌肉注射地塞米松（1或4mg/kg），连续5天，可使AQP1在mRNA和蛋白质水平的表达增加约两倍。GR拮抗剂RU-486完全抑制了地塞米松的作用。AQP1表达增加的功能对应物是跨PM的钠筛分和净超滤显著增加，这与对渗透梯度和小溶质通透性缺乏影响形成对比。后一观察结果反映了皮质类固醇对PM中一氧化氮合酶（NOS）活性和内皮型NOS同工型表达缺乏影响。总之，皮质类固醇诱导PM毛细血管内皮中AQP1表达，这表现为跨细胞水通透性和超滤增加。这些数据强调了AQP1在PD过程中的关键作用，并表明对AQP1的药理调节可能为控制跨PM的水通透性提供一个靶点。
