Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Inhibition of soluble epoxide hydrolase attenuates a high-fat diet-mediated renal injury by activating PAX2 and AMPK.

Authors: Luo, Ying; Wu, Ming-Yu; Deng, Bing-Qing; Huang, Jian; Hwang, Sung Hee; Li, Meng-Yuan; Zhou, Chun-Yu; Zhang, Qian-Yun; Yu, Hai-Bo; Zhao, Da-Ke; Zhang, Guodong; Qin, Ling; Peng, Ai; Hammock, Bruce D; Liu, Jun-Yan

Published In Proc Natl Acad Sci U S A, (2019 03 12)

Abstract: A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in Mcp-1, and decrease in both Pax2 and Ampk in murine renal mesangial cells (mRMCs) time- and dose-dependently. Also, 14(15)-EET (a major substrate of sEH), but not its sEH-mediated metabolite 14,15-DHET, significantly reversed PA-induced increase in Mcp-1, and PA-induced decrease in Pax2 and Ampk. In addition, plasmid construction revealed that Pax2 may positively regulate Ampk transcriptionally in mRMCs. This study provides insights into and therapeutic target for the HFD-mediated renal injury.

PubMed ID: 30804206 Exiting the NIEHS site

MeSH Terms: Adenylate Kinase/metabolism*; Animals; Cytochrome P-450 Enzyme System/metabolism; Diet, High-Fat*; Disease Models, Animal; Eicosanoids/metabolism; Enzyme Inhibitors/pharmacology; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Hypertrophy; Kidney/injuries*; Kidney/pathology; Mesangial Cells/drug effects; Mesangial Cells/metabolism; Mesangial Cells/pathology; Mice; PAX2 Transcription Factor/metabolism*; Palmitic Acid; Phenylurea Compounds/pharmacology; Piperidines/pharmacology; Solubility; Time Factors; Weight Gain

Back
to Top