Journal
PHARMACEUTICAL BIOLOGY
Volume 57, Issue 1, Pages 169-175Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/13880209.2019.1577464
Keywords
Renal tubulointerstitial fibrosis; transforming growth factor beta1; cell dedifferentiation; animals
Funding
- Hospital Foundation for Doctors [YB15B01]
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Context: Ursolic acid (UA; 3 beta-hydroxy-urs-12-en-28-oic acid), one of the pentacyclic triterpenoids found in various plants and herbs, possesses some beneficial effects under pathological conditions, including combating hepatic fibrosis. Objective: This study investigates the effects of UA on renal tubulointerstitial fibrosis in vivo and in vitro. Materials and methods: In vivo, 24 male C57BL6 mice were divided into four groups. Eighteen mice were subjected to unilateral ureteral obstruction (UUO) and the remaining six sham-operated mice served as control. UUO mice received either vehicle or UA (50 or 100 mg/kg) by gastric gavage for 6 days. In vitro, HK-2 cells were treated with 10 or 50 mu M UA and 10 ng/mL recombinant human transforming growth factor-beta 1 (TGF-beta 1). The molecular mechanisms of fibrosis were investigated. Results: UUO induced marked interstitial collagen I and fibronectin deposition and epithelial-mesenchymal transition (EMT), as evidenced by increased alpha-smooth muscle actin (alpha-SMA) and decreased E-cadherin. However, UA treatment significantly reduced collagen I and fibronectin accumulation in the fibrotic kidney. UA treatment also decreased alpha-SMA and preserved E-cadherin in vivo. In vitro, TGF-beta 1-treated HK-2 cells demonstrated elevated alpha-SMA, snail1, slug, TGF-beta 1, and p-smad3, as well as diminished E-cadherin. UA pretreatment prevented E-cadherin loss and diminished alpha-SMA expression in HK-2 cells. UA downregulated mRNA expression of snail1 and slug. UA also lowered TGF-beta 1 protein expression and p-Smad3 in HK-2 cells. Conclusions: UA attenuated renal tubulointerstitial fibrosis by inhibiting EMT, and such inhibition may be achieved by decreasing profibrotic factors. UA may be a novel therapeutic agent for renal fibrosis.
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