Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.
Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.
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低剂量紫杉醇通过下调 miR-192 改善残肾模型中的纤维化
DOI：
10.1002/path.2961
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发表时间：
2011-11
影响因子：
7.3
通讯作者：
Kanwar, Yashpal S.
中科院分区：
文献类型：
--
作者：
Sun, Lin;Zhang, Dongshan;Liu, Fuyou;Xiang, Xudong;Ling, Guanghui;Xiao, Li;Liu, Yinghong;Zhu, Xuejing;Zhan, Ming;Yang, Yeyi;Kondeti, Vinay K.;Kanwar, Yashpal S.
转化生长因子 (TGF)-β 已被证明在肾小管间质纤维化的发展中发挥核心作用，可以通过紫杉醇治疗来纠正。紫杉醇可以调节 microRNA (miR) 的生物学特性。我们假设紫杉醇可能通过抑制 TGF-β 诱导的 miR 来减轻残肾病大鼠模型中的肾纤维化。大鼠每组12只，接受5/6肾切除术并接受小剂量紫杉醇腹腔注射。 8周时评估肾功能。通过实时聚合酶链式反应 (TRT-PCR) 和免疫荧光显微镜评估 TGF-β 信号级联和 ECM 蛋白。具有残肾的动物出现高血压，紫杉醇治疗并未缓解高血压。然而，紫杉醇治疗导致蛋白尿反应减弱，血清 BUN、肌酐水平和尿蛋白：肌酐比值降低，肌酐清除率正常化。这些作用还伴随着 Smad2/3 激活的抑制、肾纤维化的减弱以及整合素连接激酶 (ILK)、COL(I)A1、COL(IV)A2 和 α-SMA 表达的正常化。此外，紫杉醇下调了残肾中 miR-192、miR-217 和 miR -377 的表达，而 miR-15 则上调。体外，在肾小管上皮细胞 (NRK-52E) 中，紫杉醇还抑制 TGF-β1 诱导的 Smad2/3 激活，并使 ILK、COL(I)A1、COL(IV)A2 和 α-SMA 表达正常化。此外，ChIP 分析表明紫杉醇抑制 Smad3 介导的 miR-192 转录活性。 NRK-52E 中 miR-192 的过度表达模拟了残肾中观察到的变化，而培养基中包含 miR-192 抑制剂则阻断了 TGF-β1 诱导的 COL(I)A1 和 COL(IV)A2 表达，而 ILK 和 α-SMA 不受影响。这些数据表明低剂量紫杉醇通过调节 miR-192 病理学和 TGF-β/Smad 信号传导改善肾纤维化。版权所有 © 2011 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Transforming growth factor (TGF)-β has been shown to play a central role in the development of tubulointerstitial fibrosis, which can be corrected via treatment with paclitaxel. The biology of microRNA (miR) can be modulated by paclitaxel. We hypothesized that paclitaxel may attenuate renal fibrosis in a rat model of remnant kidney disease by inhibiting TGF-β induced-miRs. Rats in groups of 12 were subjected to 5/6 nephrectomy and received low-dose intraperitoneal injection of paclitaxel. Renal functions were assessed at 8 weeks. The TGF-β signalling cascade and ECM proteins were evaluated by real-time polymerase chain reaction (TRT–PCR) and immunofluorescence microscopy. Animals with remnant kidneys developed hypertension, which was not relieved with paclitaxel treatment. However, paclitaxel treatment resulted in dampening the proteinuric response, reduction in serum BUN, creatinine levels and urine protein : creatinine ratio and normalization of creatinine clearance. These effects were accompanied by the inhibition of Smad2/3 activation, attenuation of renal fibrosis and normalization of integrin-linked kinase (ILK), COL(I)A1, COL(IV)A2 and α-SMA expression. Also, paclitaxel down-regulated the expression of miR-192, miR-217 and miR -377, while miR-15 was up-regulated in the remnant kidney. In vitro, in tubular epithelial cells (NRK-52E), paclitaxel also inhibited TGF-β1-induced Smad2/3 activation and normalized ILK, COL(I)A1, COL(IV)A2 and α-SMA expression. Furthermore, ChIP analyses indicated that Taxol suppressed Smad3-mediated miR-192 transcriptional activity. Over-expression of miR-192 in NRK-52E mimicked the changes seen in the remnant kidney, while inclusion of miR-192 inhibitor in the culture medium blocked TGF-β1-induced COL(I)A1 and COL(IV)A2 expression, while ILK and α-SMA were unaffected. These data suggest that low-dose paclitaxel ameliorates renal fibrosis via modulating miR-192 pathobiology and TGF-β/Smad signalling. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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影响因子：
8.3
作者：
Liao, Tang-Dong;Yang, Xiao-Ping;Carretero, Oscar A.
通讯作者：
Carretero, Oscar A.
影响因子：
16
作者：
Dong, CM;Li, ZR;Goldschmidt-Clermont, PJ
通讯作者：
Goldschmidt-Clermont, PJ
影响因子：
19.6
作者：
Ng, YY;Huang, TP;Lan, HY
通讯作者：
Lan, HY
DOI：
10.1165/rcmb.2003-0063oc
发表时间：
2003-09-01
影响因子：
6.4
作者：
Hu, B;Wu, Z;Phan, SH
通讯作者：
Phan, SH
影响因子：
13.6
作者：
Chung, Arthur C. K.;Huang, Xiao R.;Lan, Hui Y.
通讯作者：
Lan, Hui Y.