Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
PLoS One. 2012;7(2):e31492. doi: 10.1371/journal.pone.0031492. Epub 2012 Feb 27.
Peritoneal fibrosis is a frequent complication of peritoneal dialysis following repeated low grade inflammatory and pro-fibrotic insults. This pathological process may lead to ultrafiltration failure and eventually to the discontinuing of the therapy. Fibrosis is linked to epithelial to mesenchymal transition (EMT) of the peritoneal mesothelial cells, which acquire invasive and fibrogenic abilities. Here, we analyzed the role of the transforming growth factor-activated kinase-1 (TAK1) in the EMT of primary mesothelial cells from human peritoneum. The inhibition of TAK1 in mesenchymal-like mesothelial cells from the effluents of patients undergoing peritoneal dialysis led to the reacquisition of the apical to basolateral polarity, to increased expression of epithelial and to down-regulation of mesenchymal markers. TAK1 inhibition also resulted in decreased migratory/invasive abilities of effluent-derived mesothelial cells. Simultaneous inhibition of ERK1/2 and TAK1 pathways did not lead to an additive effect in the reacquisition of the epithelial phenotype. Inhibition of TAK1 also blocked EMT in vitro and reduced the levels of PAI-1, which is involved in fibrosis and invasion. Analysis of signalling pathways downstream of TAK1 involved in EMT induction, showed that TAK1 inhibition reduced the transcriptional activity of NF-κB and Smad3, as well as the phosphorylation of c-jun, while enhancing Smad1-5-8 activity. These results demonstrate that TAK1 is a cross-point in a network including different pro-EMT transcription factors, such as NF-κB, Snail, AP-1 and Smads. The identification of TAK1 as a main biochemical mediator of EMT and fibrosis in mesothelial cells from human peritoneum and the study of signalling pathways induced by its activity may be relevant in the design of new therapies aimed to counteract peritoneal fibrosis.
腹膜纤维化是腹膜透析后反复发生低度炎症和促纤维化损伤的常见并发症。这一病理过程可导致超滤衰竭，并最终导致治疗中断。纤维化与腹膜间皮细胞的上皮间质转化（EMT）有关，间皮细胞获得侵袭和纤维化能力。在这里，我们分析了转化生长因子激活激酶 1（TAK1）在人腹膜间皮细胞 EMT 中的作用。在接受腹膜透析的患者流出物中的间充质样间皮细胞中抑制 TAK1 可导致顶端到基底外侧极性的重新获得、上皮标志物的表达增加和间充质标志物的下调。TAK1 抑制也导致流出物衍生的间皮细胞迁移/侵袭能力降低。ERK1/2 和 TAK1 通路的同时抑制在获得上皮表型方面没有叠加效应。TAK1 抑制还阻断了 EMT，并降低了参与纤维化和侵袭的 PAI-1 水平。对 TAK1 下游参与 EMT 诱导的信号通路的分析表明，TAK1 抑制减少了 NF-κB 和 Smad3 的转录活性以及 c-jun 的磷酸化，同时增强了 Smad1-5-8 的活性。这些结果表明 TAK1 是一个包含不同 EMT 转录因子（如 NF-κB、Snail、AP-1 和 Smads）的网络中的交汇点。确定 TAK1 是人类腹膜间皮细胞 EMT 和纤维化的主要生化介质，以及研究其活性诱导的信号通路，可能与设计旨在对抗腹膜纤维化的新疗法有关。
