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

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.

In vitro and in vivo evaluation of effect of excipients in local delivery of paclitaxel using microporous infusion balloon catheters

“…This result is in agreement with the literature as PAT significantly decreases the SM a-actin expression. 21,22 Also, in this study, no significant difference in the SM a-actin expression was observed between the cells treated with Cremophor-PAT and nab-PAT.…”

PEG-<em>b</em>-(PELG-<em>g</em>-PLL) nanoparticles as TNF-&alpha; nanocarriers: potential cerebral ischemia/reperfusion injury therapeutic applications

“…Exposure to local cerebral ischemia induces protein expression of ICAM-1 and GFAP. 37,51 Our data reveal that the expression levels of ICAM-1 and GFAP after I/R-induced cerebral injury were remarkably increased, while they were depressed after pretreatment with TNF-α or TNF-α/PEGb-(PELG-g-PLL). TNF-α or TNF-α/PEG-b-(PELG-g-PLL) pretreatment had a neuroprotective effect against BI/RI, and this effect was related to the inhibition of oxidative stress, inflammation, and apoptosis via reduction in both the expression of ICAM-1, GFAP, and caspase-3 and the levels of IL-6, IL-8, NO, and MDA, as well as increases in SOD activity and the levels of IL-4 and IL-10.…”

Periplaneta Americana Extract May Attenuate Renal Fibrosis through Inhibiting Janus Tyrosine Kinase 2/Signal Transducer and Activator of Transcription 3 Pathway

“…It has been indicated that fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation [12]. And Zhang et al[8] found that Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling. In our study, when treated with PAE, both in vivo and in vitro, the JAK2 and STAT3 tyrosine phosphorylation was inhibited and after that the process of renal fibrosis has been delayed.…”

“…And it has been reported to mediate various cellular functions, including gene activation, cell differentiation, cell survival, and proliferation [7]. STAT3 is an important member of the STAT family and mediates cell survival and proliferation [8]. Increasing evidence has suggested that the STAT3 pathway is highly related to renal fibrosis.…”