Renal fibrosis is a contributor to chronic kidney disease and an important predictor of long-term prognosis. We developed a dual soluble epoxide hydrolase inhibitor-PPAR-γ agonist (sEHi/PPAR-γ), RB394, and investigated its ability to attenuate renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. RB394 efficacy was compared to an sEH inhibitor (sEHi), a PPAR-γ agonist rosiglitazone (Rosi), or their combination (sEHi + Rosi). All interventional treatments were administrated in drinking water 3 days after UUO induction surgery and continued for 7 days. UUO mice developed renal fibrosis with higher collagen formation and RB394 significantly attenuated fibrosis (P < 0.05). Renal expression of α-smooth muscle actin (α-SMA) was elevated in UUO mice and all treatments except sEHi significantly attenuated renal α-SMA expression. Renal mRNA expression fibrotic and fibrosis regulators were higher in UUO mice and RB394 and sEHi + Rosi treatments attenuated their expression. Renal inflammation was evident in UUO mice with increased infiltration of CD45 and F4/80 positive cells. RB394 and sEHi + Rosi treatments attenuated renal inflammation in UUO mice. UUO mice had renal tubular and vascular injury. Renal tubular and vascular injuries were attenuated to a greater extent by RB394 and sEHi + Rosi than sEHi or Rosi treatment alone. Renal mRNA expression of oxidative stress markers were significantly higher in UUO mice (P < 0.05). RB394 and sEHi + Rosi attenuated expression of oxidative stress markers to a greater extent than other interventional treatments (P < 0.05). These findings demonstrate that RB394 can attenuate renal fibrosis by reducing renal inflammation, oxidative stress, tubular injury, and vascular injury. In conclusion, RB394 demonstrates exciting potential as a therapeutic for renal fibrosis and chronic kidney disease.

肾纤维化是慢性肾病的一个促成因素，也是长期预后的重要预测因素。我们开发了一种双重可溶性环氧化物水解酶抑制剂-PPAR-γ 激动剂 (sEHi/PPAR-γ)，RB394，并研究了其在小鼠单侧输尿管梗阻 (UUO) 模型中减轻肾纤维化的能力。RB394 的功效与 sEH 抑制剂 (sEHi)、PPAR-γ 激动剂罗格列酮 (Rosi) 或它们的组合 (sEHi + Rosi) 进行了比较。所有介入治疗均于UUO诱导术后3天饮水给药，持续7天。UUO 小鼠发生肾纤维化，胶原形成较多，RB394 显着减轻纤维化（P < 0.05）。α-平滑肌肌动蛋白（α-SMA）的肾脏表达在 UUO 小鼠中升高，除 sEHi 之外的所有治疗都显着减弱了肾脏 α-SMA 的表达。UUO 小鼠的肾 mRNA 表达纤维化和纤维化调节因子较高，RB394 和 sEHi + Rosi 治疗减弱了它们的表达。UUO 小鼠的肾脏炎症明显，CD45 和 F4/80 阳性细胞浸润增加。RB394 和 sEHi + Rosi 治疗减轻了 UUO 小鼠的肾脏炎症。UUO 小鼠有肾小管和血管损伤。RB394 和 sEHi + Rosi 比单独使用 sEHi 或 Rosi 治疗更能减轻肾小管和血管损伤。UUO 小鼠肾脏氧化应激标志物的 mRNA 表达显着升高（P < 0.05）。RB394 和 sEHi + Rosi 比其他介入治疗更大程度地减弱氧化应激标志物的表达（P < 0.05）。这些发现表明 RB394 可以通过减少肾脏炎症来减轻肾脏纤维化，氧化应激、肾小管损伤和血管损伤。总之，RB394 显示出作为治疗肾纤维化和慢性肾病的令人兴奋的潜力。