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Epoxyeicosatrienoic Acid Analogs Reduce Renal Fibrosis By Reducing Epithelial‐To Mesenchymal‐Transition
Author(s) -
Khan Md. Abdul Hye,
Sharma Amit,
Falck John R.,
Imig John D.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1195.4
Subject(s) - hydroxyproline , kidney , myofibroblast , fibrosis , epithelial–mesenchymal transition , kidney disease , medicine , pathology , endocrinology , urology , metastasis , cancer
Epoxyeicosatrienoic acids (EETs) are CYP epoxygenase metabolites of arachidonic acid that demonstrate diverse biological actions including kidney protection. Chronic kidney disease (CKD) progresses to end‐stage renal disease and common pathways leading to renal fibrosis are major contributors to CKD. Renal epithelial‐to‐mesenchymal transition (EMT) plays a critical role in renal fibrosis and CKD. We investigated the ability of EET analogs (EET‐A and EET‐B) to reduce EMT and protect from kidney fibrosis in a mouse unilateral ureteral obstruction (UUO) model. C57/BL6 male mice underwent sham or UUO surgical procedure and were grouped (n=6–8) as Sham‐Vehicle, UUO‐Vehicle, UUO‐EET‐A, and UUO‐EET‐B. EET analogs (10mg/kg/d) or vehicle administrated in drinking water for 10 days following UUO surgery. Kidneys were collected for mRNA, protein, and biochemical analysis and histopathological evaluation. Kidney histopathology in UUO mice revealed a marked renal fibrosis with 80% higher kidney collagen positive area compared to Sham group. EET analogs significantly reduced kidney collagen positive area by 50–60%. Accordingly, kidney hydroxyproline content was also higher in UUO (6.2±0.4μg/10mg) compared to Sham group (2.5±0.1μg/10mg), and EET analogs reduced hydroxyproline levels by ~20–40%. Moreover, immunopositive kidney area and mRNA expression of an important renal fibrosis and myofibroblast marker, α‐smooth muscle actin (SMA), was higher in UUO compared to Sham group, and EET‐A and EET‐B reduced SMA levels. Interestingly, in UUO group renal mRNA expression of the epithelial marker E‐cadherin was reduced by 30% compared to Sham group, and EET analogs increased E‐cadherin expression. Renal mRNA expression of mesenchymal markers α‐SMA, collagen IV, and fibronectin were higher in UUO vehicle mice compared to Sham group, and EET analogs reduced expression of mesenchymal markers. Overall, our results demonstrate that EET analogs reduce renal fibrosis in UUO by inhibiting renal EMT.