文献详情
Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3 beta signaling
文献类型期刊论文
作者Deng, Bing-Qing[1];Luo, Ying[2];Kang, Xin[3];Li, Chang-Bin[4];Morisseau, Christophe[5];Yang, Jun[6];Lee, Kin Sing Stephen[7];Huang, Jian[8];Hu, Da-Yong[9];Wu, Ming-Yu[10];Peng, Ai[11];Hammock, Bruce D.[12];Liu, Jun-Yan[13]
机构
通讯作者Liu, JY (reprint author), Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Ctr Nephrol & Metabol, Shanghai 210072, Peoples R China.; Liu, JY (reprint author), Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Div Nephrol & Rheumatol, Shanghai 210072, Peoples R China.; Hammock, BD (reprint author), Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA.; Hammock, BD (reprint author), Univ Calif Davis, Comprehens Canc Ctr, Davis, CA 95616 USA.
2017
期刊名称PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA影响因子和分区
114
47
页码范围12608-12613
增刊正刊
学科临床医学
收录情况SCI(E)(WOS:000416503700077)  PubMed(29109264)  
所属部门医院
语言外文
ISSN0027-8424
DOI10.1073/pnas.1705615114
被引频次1
人气指数232
浏览次数231
基金NIEHS Superfund Grant [P42 ES04699]; NIH/National Heart, Lung, and Blood Institute Grant [R01 HL59699-06A1]; National Institute of Environmental Health Sciences (NIEHS) [R01 ES02710]; NIEHS [R00 ES024806]; Translational Technology Grant from the University of California Davis Medical Center; National Natural Science Foundation of China (NSFC) [81470588, 81100090]
关键词epoxyeicosatrienoic acid; epoxydocosapentaenoic acid; renal tubular epithelial cells; siRNA; GSK3 beta phosphorylation
摘要Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14(15)-epoxyeicosatrienoic add [14(15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (l/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated l/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the l/R-caused reduction in glycogen synthase kinase 3 beta (GSK3 beta) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3 beta phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3 beta phosphorylation in mRTECs. In addition, 19(20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in l/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3 beta phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.
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