Lopez-Anton Melisa, Lambie Mark, Lopez-Cabrera Manuel, Schmitt Claus P, Ruiz-Carpio Vicente, Bartosova Maria, Schaefer Betti, Davies Simon, Stone Timothy, Jenkins Robert, Taylor Philip R, Topley Nicholas, Bowen Timothy, Fraser Donald
Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
Keele University, Keele, United Kingdom.
Am J Pathol. 2017 Jul;187(7):1537-1550. doi: 10.1016/j.ajpath.2017.03.007. Epub 2017 May 9.
Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.
腹膜透析（PD）是终末期肾病患者的一种挽救生命的肾脏替代治疗方式。间皮细胞（MCs）覆盖腹膜腔，并有助于确定腹膜对治疗相关损伤的反应，这是治疗失败的主要原因。微小RNA（miRNAs）是重要的调节因子，但其在腹膜纤维化中的作用尚不清楚。在本研究中，miR-21是原代MCs中含量最丰富的miRNAs之一，并且在促纤维化细胞因子转化生长因子-β1作用下以及在表现出间充质表型变化的PD流出液来源的MCs中上调。与健康对照相比，在PD患者的腹膜活检标本中发现miR-21增加（生物相容性PD，5.86倍，P = 0.0001；传统PD，7.09倍，P < 0.0001，每组n = 11）。在230例患者的PD流出液中，与新开始接受治疗的患者相比，长期接受治疗的患者miR-21更高（n = 230，miR-21 3.26倍，P = 0.001），并且与艾考糊精的使用（R = 0.52；95%可信区间，0.20 - 0.84）、腹膜炎次数（R = 0.16；95%可信区间，0.03 - 0.29）和透析液细胞因子相关。miR-21下调程序性细胞死亡蛋白4，与健康对照相比，PD患者腹膜活检标本中程序性细胞死亡蛋白4减少。鉴定出了新的miR-21靶标，其可能在PD纤维化过程中起重要作用。这些数据确定miR-21是腹膜纤维化的重要效应因子，并且是接受PD治疗患者透析流出液中腹膜变化的有前景的生物标志物。
