Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition.
Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition.
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DOI：
10.3389/fphar.2017.00406
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发表时间：
2017
影响因子：
5.6
通讯作者：
Imig JD
中科院分区：
文献类型：
--
作者：
Skibba M;Hye Khan MA;Kolb LL;Yeboah MM;Falck JR;Amaradhi R;Imig JD
肾纤维化是慢性肾脏疾病的重要病理生理学事件，与肾上皮细胞向间质细胞转化（EMT）有关。环氧二十碳三烯酸（Epoxyeicosatrienoic acids，ESTs）是Cyp环氧合酶花生四烯酸代谢产物，具有保护肾脏的生物学作用。在此，我们研究了14，15-EET及其合成类似物EET-A减少单侧输尿管梗阻（UUO）诱导的肾纤维化的能力。C57/BL 6雄性小鼠经历假手术或UUO手术程序，并在渗透泵中用14，15-EET或EET-A处理（i. p.）术后10天，UUO手术。与假手术组相比，UUO小鼠表现出肾纤维化，肾脏胶原蛋白阳性面积高80%，α-平滑肌肌动蛋白（SMA）阳性肾脏面积高70%。作为胶原蛋白含量的量度，UUO组的肾羟脯氨酸含量（6.4 ± 0.5 μg/10 mg）也高于假手术组（2.5 ± 0.1 μg/10 mg）。沿着显著的肾纤维化，UUO小鼠的EET产生Cyp环氧合酶的肾表达减少。内源性14，15-EET或EET-A通过减少肾脏胶原阳性面积（50-60%）、羟脯氨酸含量（50%）和肾脏α-SMA阳性面积（85%），在UUO中显示出抗纤维化作用。在UUO小鼠中，与假手术组相比，EMT诱导剂Snail 1和ZEB 1的肾脏表达更高。因此，与假手术小鼠相比，UUO中肾上皮标记物E-钙粘蛋白表达减少，间充质标记物表达升高。有趣的是，EET-A通过降低肾脏Snail 1和ZEB 1的表达来减少UUO小鼠的EMT。EET-A治疗还对抗了肾E-钙粘蛋白表达的降低，并显著降低了UUO小鼠中几种主要的肾间充质/肌成纤维细胞标志物。总之，我们的结果表明，EET-A是一种新型抗纤维化药物，通过减少肾脏EMT来减少肾纤维化。
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 α-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 μg/10 mg) compared to sham group (2.5 ± 0.1 μg/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 α-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.