Journal
KIDNEY RESEARCH AND CLINICAL PRACTICE
Volume 36, Issue 4, Pages 329-341Publisher
KOREAN SOC NEPHROLOGY
DOI: 10.23876/j.krcp.2017.36.4.329
Keywords
Epithelial-mesenchymal transition; Endothelial dysfunction; Endothelial-to-mesenchymal transition; Kidney fibrosis; Soluble epoxide hydrolase
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Funding
- Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea [HI11C1291]
- Korean Society of Nephrology (BAXTER)
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Background: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents. Methods: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. Results: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks. Treatment with AUDA significantly ameliorated tubulointerstitial fibrosis by reducing fibroblast mobilization and enhancing endothelial cell activity. In an in vitro model of endothelial-to-mesenchymal transition (EndMT) using human vascular endothelial cells (HUVECs), AUDA prevented the morphologic changes associated with EndMT and reduced expression of fibroblast-specific protein 1. Furthermore, HUVECs activated by AUDA prevented the epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in a co-culture system. Conclusion: Our findings suggest that regulation of sEH is a potential target for therapies aimed at delaying the progression of kidney fibrosis by inhibiting EndMT and EMT.
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