Low‐dose paclitaxel ameliorates renal fibrosis by suppressing transforming growth factor‐β1‐induced plasminogen activator inhibitor‐1 signaling. Issue 7 (July 2016)

• Record Type: Journal Article
• Authors: Jung, Eun Sook; Lee, Jeonghwan; Heo, Nam Ju; Kim, Sejoong; Kim, Dong Ki; Joo, Kwon Wook; Han, Jin Suk
• Is Part Of: Nephrology. Volume 21:Issue 7(2016)
• Page Start: 574
• Page End: 582
• Publication Date: 2016-07
• Subjects: fibrosis -- mitogen‐activated protein kinases -- paclitaxel -- plasminogen activator inhibitor‐1 -- smad proteins; Nephrology -- Periodicals; Kidneys -- Diseases -- Periodicals; Nephrologists -- Periodicals; 616.61; 616.61
• DOI: 10.1111/nep.12747
• Languages: English
• ISSNs: 1320-5358

Abstract

Abstract: 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. 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.