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2017 ; 8
(ä): 406
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Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing
Epithelial-to-Mesenchymal Transition
#MMPMID28713267
Skibba M
; Hye Khan MA
; Kolb LL
; Yeboah MM
; Falck JR
; Amaradhi R
; Imig JD
Front Pharmacol
2017[]; 8
(ä): 406
PMID28713267
show ga
Renal fibrosis, which is a critical pathophysiological event in chronic kidney
diseases, is associated with renal epithelial-to-mesenchymal transition (EMT).
Epoxyeicosatrienoic acids (EETs) are Cyp epoxygenase arachidonic acid metabolites
that demonstrate biological actions that result in kidney protection. Herein, we
investigated the ability of 14,15-EET and its synthetic analog, EET-A, to reduce
kidney fibrosis induced by unilateral ureter obstruction (UUO). C57/BL6 male mice
underwent sham or UUO surgical procedures and were treated with 14,15-EET or
EET-A in osmotic pump (i.p.) for 10 days following UUO surgery. UUO mice
demonstrated renal fibrosis with an 80% higher kidney-collagen positive area and
70% higher ?-smooth muscle actin (SMA) positive renal areas compared to the sham
group. As a measure of collagen content, kidney hydroxyproline content was also
higher in UUO (6.4 ± 0.5 ?g/10 mg) compared to sham group (2.5 ± 0.1 ?g/10 mg).
Along with marked renal fibrosis, UUO mice had reduced renal expression of EET
producing Cyp epoxygenase enzymes. Endogenous 14,15-EET or EET-A demonstrated
anti-fibrotic action in UUO by reducing kidney-collagen positive area (50-60%),
hydroxyproline content (50%), and renal ?-SMA positive area (85%). In UUO mice,
renal expression of EMT inducers, Snail1 and ZEB1 were higher compared to sham
group. Accordingly, renal epithelial marker E-cadherin expression was reduced and
mesenchymal marker expression was elevated in the UUO compared to sham mice.
Interestingly, EET-A reduced EMT in UUO mice by deceasing renal Snail1 and ZEB1
expression. EET-A treatment also opposed the decrease in renal E-cadherin
expression and markedly reduced several prominent renal mesenchymal/myofibroblast
markers in UUO mice. Overall, our results demonstrate that EET-A is a novel
anti-fibrotic agent that reduces renal fibrosis by decreasing renal EMT.
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