期刊
TOXICOLOGICAL SCIENCES
卷 160, 期 2, 页码 217-229出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfx183
关键词
perfluorooctanesulfonate; peroxisome proliferator-activated receptor gamma; silent information regulator T1; epithelial-to-mesenchymal transition; renal fibrosis
类别
资金
- Ministry of Science and Technology of Taiwan [MOST103-2314-B-585-002, MOST105-2628-B-038-010-MY3]
- En-Chu-Kong Hospital (a regional hospital in the Taipei County) [ECKH10403, ECKH10404]
We have previously reported that perfluorooctanesulfonate (PFOS) causes cell apoptosis in renal tubular epithelial cells (RTCs). Here, we extend our findings and provide evidence of epithelial-mesenchymal transition (EMT)-associated renal fibrosis caused by PFOS and the protection by L-carnitine. Our results demonstrate that PFOS increased the expression of EMT and renal injury biomarkers (eg, N-cadherin, vimentin, Snail, Kim1, and Lcn2). In addition, PFOS caused EMT induction through Sirt1-mediated PPAR gamma deacetylation and inactivation. L-carnitine reversed the EMT induction caused by PFOS and alleviated PFOS-mediated increases in cell migration by reactivating PPAR gamma through the inhibition of Sirt1 activity. The critical role of Sirt1 in this process was validated by using Sirt1 overexpression, resveratrol (a pharmacologic activator of Sirt1), nicotinamide (a Sirt1 inhibitor) and siSirt1. Nicotinamide and siSirt1, but not Sirt1 overexpression and resveratrol, alleviated PFOS-mediated EMT induction, suggesting that increased Sirt1 activity contributed to the alterations. Furthermore, through PPAR gamma overexpression and pharmacologic interventions, we validated the crucial role of increased PPAR gamma deacetylation caused by aberrant increased Sirt1 activity in RTC transformation. Similar to PPAR gamma overexpression, rosiglitazone (a PPAR gamma agonist) alleviated the effects of PFOS on the EMT-related features, whereas GW9662 (a PPAR gamma antagonist) mimicked the effects. The protective effect of L-carnitine was also verified in amousemodel of chronic PFOS exposure, in which decreased EMT biomarker levels and renal fibrosis by L-carnitine were observed in Western blot and histological analyses. Accordingly, L-carnitine alleviated EMT-associated renal fibrosis caused by PFOS through a Sirt1- and PPAR gamma-dependent mechanism.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据