Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
J Pathol. 2011 Nov;225(3):364-77. doi: 10.1002/path.2961. Epub 2011 Aug 24.
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.
转化生长因子 (TGF)-β 在肾小管间质纤维化的发展中发挥核心作用，而紫杉醇的治疗可以纠正这一作用。微 RNA (miR) 的生物学可以通过紫杉醇来调节。我们假设紫杉醇可能通过抑制 TGF-β 诱导的 miR 来减轻剩余肾脏疾病大鼠模型中的肾纤维化。12 只大鼠分为几组，进行 5/6 肾切除术，并接受低剂量腹腔内紫杉醇注射。8 周时评估肾功能。通过实时聚合酶链反应 (TRT-PCR) 和免疫荧光显微镜评估 TGF-β 信号级联和 ECM 蛋白。剩余肾脏的动物发生高血压，紫杉醇治疗不能缓解。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。这些作用伴随着 Smad2/3 激活的抑制、肾纤维化的减轻和整合素连接激酶 (ILK)、COL(I)A1、COL(IV)A2 和 α-SMA 表达的正常化。此外，紫杉醇下调 miR-192、miR-217 和 miR-377 的表达，而 miR-15 在剩余肾脏中上调。在体外，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 Taxol 抑制 Smad3 介导的 miR-192 转录活性。NRK-52E 中转录本 miR-192 的过表达模拟了剩余肾脏中观察到的变化，而在培养基中加入 miR-192 抑制剂阻断了 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 病理生物学和 TGF-β/Smad 信号转导来改善肾纤维化。
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