title: Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.
abstract: 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.
authors: Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. sunlinnwu11@163.com
authors: Lin
authors: L
authors: Sun
authors: Dongshan
authors: D
authors: Zhang
authors: Fuyou
authors: F
authors: Liu
authors: Xudong
authors: X
authors: Xiang
authors: Guanghui
authors: G
authors: Ling
authors: Li
authors: L
authors: Xiao
authors: Yinghong
authors: Y
authors: Liu
authors: Xuejing
authors: X
authors: Zhu
authors: Ming
authors: M
authors: Zhan
authors: Yeyi
authors: Y
authors: Yang
authors: Vinay K
authors: VK
authors: Kondeti
authors: Yashpal S
authors: YS
authors: Kanwar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003404:Creatinine / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006977:Hypertension, Renal / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009392:Nephrectomy / Q000379:methods; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D035683:MicroRNAs; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D050257:Tubulin Modulators; D003404:Creatinine; D017239:Paclitaxel