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Low‐dose paclitaxel ameliorates renal fibrosis by suppressing transforming growth factor‐β1‐induced plasminogen activator inhibitor‐1 signaling
Author(s) -
Jung Eun Sook,
Lee Jeonghwan,
Heo Nam Ju,
Kim Sejoong,
Kim Dong Ki,
Joo Kwon Wook,
Han Jin Suk
Publication year - 2016
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1111/nep.12747
Subject(s) - paclitaxel , plasminogen activator inhibitor 1 , medicine , plasminogen activator , transforming growth factor , extracellular matrix , western blot , fibronectin , fibrosis , endocrinology , pharmacology , chemistry , chemotherapy , biochemistry , gene
Aim To investigate the effect of microtubule stabilization with low‐dose paclitaxel on renal fibrosis, focusing on the transforming growth factor‐β1 (TGF‐β1)‐induced plasminogen activator inhibitor‐1 (PAI‐1) signaling cascade. Methods Forty‐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 0.3 mg/kg intraperitoneal dose of paclitaxel or vehicle twice per week for 14 days. 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‐β1 were incubated with 0, 1 and 2 nM paclitaxel for 24 and 72 hours. Histological changes were assessed using periodic acid‐Schiff and Masson's trichrome. The TGF‐β1‐induced PAI‐1 signaling and status of extracellular matrix proteins were evaluated by western blot analysis. Results In the UUO kidneys, paclitaxel significantly attenuated tubular damage and interstitial collagen deposition, as well as α‐smooth muscle actin (α‐SMA), TGF‐β1 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‐β1‐treated IMCD cells, treatment with 1 and 2 nM paclitaxel for 72 h reduced fibronectin, α‐SMA and PAI‐1 protein expression. Moreover, a 2 nM dose of paclitaxel for 24 h significantly inhibited the TGF‐β1‐stimulated activation of Smad2/3, JNK and ERK1/2 in IMCD cells. Conclusion Paclitaxel at low non‐cytotoxic doses ameliorates renal fibrosis by inhibiting multiple steps in the TGF‐β1‐induced PAI‐1 signaling including Smads and mitogen‐activated protein kinases.