Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling.
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.
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China ; Department of Nephrology, Central South University, Changsha, Hunan, People's Republic of China.
Lei
L
Zhang
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Xuan
X
Xu
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Ruhao
R
Yang
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Jingwen
J
Chen
Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
Shixuan
S
Wang
Department of Minimally Invasive Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Junqin
J
Yang
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Xudong
X
Xiang
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Zhibiao
Z
He
Department of Nephrology, Harbin First Hospital, Harbin, Heilongjiang, People's Republic of China.
Yu
Y
Zhao
Department of Nephrology, Central South University, Changsha, Hunan, People's Republic of China ; Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
Zheng
Z
Dong
Department of Emergency Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Dongshan
D
Zhang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014404:Tubulin; D017239:Paclitaxel
STAT3; UUO; paclitaxel; tubulin; tubulointerstitial fibrosis