Low-dose paclitaxel ameliorates renal fibrosis by suppressing transforming growth factor-1-induced plasminogen activator inhibitor-1 signaling

Abstract

AimTo investigate the effect of microtubule stabilization with low-dose paclitaxel on renal fibrosis, focusing on the transforming growth factor-1 (TGF-1)-induced plasminogen activator inhibitor-1 (PAI-1) signaling cascade. MethodsForty-eight rats were randomly assigned to four groups: sham/vehicle, sham/paclitaxel, unilateral ureteral obstruction (UUO)/vehicle and UUO/paclitaxel. Rats were treated with a 0.3mg/kg intraperitoneal dose of paclitaxel or vehicle twice per week for 14days. Half of the rats in each group were sacrificed respectively on day 7 and 14 after operation. Inner medullar collecting duct (IMCD) cells stimulated with TGF-1 were incubated with 0, 1 and 2 nM paclitaxel for 24 and 72hours. Histological changes were assessed using periodic acid-Schiff and Masson's trichrome. The TGF-1-induced PAI-1 signaling and status of extracellular matrix proteins were evaluated by western blot analysis. ResultsIn the UUO kidneys, paclitaxel significantly attenuated tubular damage and interstitial collagen deposition, as well as -smooth muscle actin (-SMA), TGF-1 and PAI-1 protein expression. Paclitaxel also inhibited the UUO-induced activation of Smad2/3 and c-Jun N-terminal kinase (JNK). However, paclitaxel treatment did not inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) or p38 expression. In TGF-1-treated IMCD cells, treatment with 1 and 2 nM paclitaxel for 72h reduced fibronectin, -SMA and PAI-1 protein expression. Moreover, a 2 nM dose of paclitaxel for 24h significantly inhibited the TGF-1-stimulated activation of Smad2/3, JNK and ERK1/2 in IMCD cells. ConclusionPaclitaxel at low non-cytotoxic doses ameliorates renal fibrosis by inhibiting multiple steps in the TGF-1-induced PAI-1 signaling including Smads and mitogen-activated protein kinases. Summary at a Glance This paper uses a model of experimental renal fibrosis in rats to study the renoprotective effect of low dose paclitaxel, a chemotherapy agent, by inhibiting TGF-b1 and Smad signaling. The study also provides in vitro mechanistic insight into the effects of paciltaxel on TGF-b-stimulated inner medullary collecting ducts.