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Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling

Authors Zhang L, Xu X, Yang R, Chen J, Wang S, Yang J, Xiang X, He Z, Zhao Y, Dong Z, Zhang D

Received 22 January 2015

Accepted for publication 27 February 2015

Published 15 April 2015 Volume 2015:9 Pages 2139—2148

DOI https://doi.org/10.2147/DDDT.S81390

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Shu-Feng Zhou


Lei Zhang,1,2,* Xuan Xu,1,* Ruhao Yang,1,* Jingwen Chen,1 Shixuan Wang,5 Junqin Yang,3 Xudong Xiang,1 Zhibiao He,1 Yu Zhao,4 Zheng Dong,2,5 Dongshan Zhang1

1Department of Emergency Medicine, 2Department of Nephrology, 3Department of Minimally Invasive Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Nephrology, Harbin First Hospital, Harbin, Heilongjiang, People’s Republic of China; 5Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, GA, USA

*Co-first authors in this study

Abstract: Recent studies have demonstrated that paclitaxel might inhibit renal fibrosis. However, the underlying molecular mechanism remains unclear. In this study, we hypothesized that low-dose paclitaxel may block the STAT3 (signal transducer and activator of transcription 3) signaling to attenuate fibrosis in a mouse model with unilateral ureteral obstruction. Both NRK-49F cells and mice with unilateral ureteral obstruction were treated with paclitaxel. The results showed that paclitaxel treatment resulted in a dose- and time-dependent decrease in tyrosine-phosphorylated STAT3, and inhibited the expression of fibronectin, alpha-smooth muscle actin (α-SMA), and collagen I in cultured NRK-49F cells. S3I-201, an STAT3 inhibitor, also suppressed the expression of fibronectin, α-SMA, and collagen I in cultured NRK-49F cells. Mechanistically, paclitaxel treatment blocked the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation. Furthermore, paclitaxel also ameliorated renal fibrosis by down-regulating the expression of fibronectin, α-SMA, and collagen I, and suppressed the infiltration of macrophages and production of TNF-α, IL-1β, TGF-β, and ICAM-1 (intercellular adhesion molecule 1) by inhibition of STAT3 activity in obstructive nephropathy. These results suggest that paclitaxel may block the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation, consequently leading to the suppression of renal interstitial fibroblast activation and the development of renal fibrosis, and inhibition of proinflammatory cytokine production.

Keywords: UUO, tubulointerstitial fibrosis, tubulin, paclitaxel, STAT3


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