Su Xuesong, Zhou Guangyu, Wang Yanqiu, Yang Xu, Li Li, Yu Rui, Li Detian
Department of Nephrology, Shengjing Hospital, China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China.
Inflammation. 2014 Jun;37(3):729-37. doi: 10.1007/s10753-013-9791-z.
Peritoneal fibrosis is a common consequence of long-term peritoneal dialysis (PD), and peritonitis is a factor in its onset. Agonist-bound peroxisome proliferator-activated receptors (PPARs) function as key regulators of energy metabolism and inflammation. Here, we examined the effects of PPARβ/δ agonist GW501516 on peritonitis in a rat peritoneal fibrosis model. Peritoneal fibrosis secondary to inflammation was induced into uremic rats by daily injection of Dianeal 4.25% PD solutions along with six doses of lipopolysaccharide before commencement of GW501516 treatment. Normal non-uremic rats served as control, and all rats were fed with a control diet or a GW501516-containing diet. Compared to control group, exposure to PD fluids caused peritoneal fibrosis that was accompanied by increased mRNA levels of monocyte chemoattractant protein-1, tumor necrotic factor-α, and interleukin-6 in the uremic rats, and these effects were prevented by GW501516 treatment. Moreover, GW501516 was found to attenuate glucose-stimulated inflammation in cultured rat peritoneal mesothelial cells via inhibition of transforming growth factor-β-activated kinase 1 (TAK1), and nuclear factor kappa B (NFκB) signaling pathway (TAK1-NFκB pathway), a main inflammation regulatory pathway. In conclusion, inhibition of TAK1-NFκB pathway with GW501516 may represent a novel therapeutic approach to ameliorate peritonitis-induced peritoneal fibrosis for patients on PD.
腹膜纤维化是长期腹膜透析（PD）的常见后果，腹膜炎是其发病的一个因素。激动剂结合的过氧化物酶体增殖物激活受体（PPARs）作为能量代谢和炎症的关键调节因子发挥作用。在此，我们研究了PPARβ/δ激动剂GW501516对大鼠腹膜纤维化模型中腹膜炎的影响。在开始GW501516治疗前，通过每日注射4.25%的腹透液（Dianeal）以及六剂脂多糖，在尿毒症大鼠中诱导出炎症继发的腹膜纤维化。正常非尿毒症大鼠作为对照，所有大鼠均喂食对照饮食或含GW501516的饮食。与对照组相比，暴露于腹透液导致尿毒症大鼠出现腹膜纤维化，同时单核细胞趋化蛋白-1、肿瘤坏死因子-α和白细胞介素-6的mRNA水平升高，而这些影响通过GW501516治疗得以预防。此外，发现GW501516通过抑制转化生长因子-β激活激酶1（TAK1）和核因子κB（NFκB）信号通路（TAK1-NFκB通路，一种主要的炎症调节通路）来减轻培养的大鼠腹膜间皮细胞中葡萄糖刺激的炎症。总之，用GW501516抑制TAK1-NFκB通路可能代表一种新的治疗方法，用于改善接受腹膜透析的患者因腹膜炎引起的腹膜纤维化。
