Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA; Educational & Scientific Center, Institute of Biology and Medicine, Taras Shevchenko National University, Kyiv, Ukraine.
Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Prostaglandins Other Lipid Mediat. 2020 Oct;150:106472. doi: 10.1016/j.prostaglandins.2020.106472. Epub 2020 Jun 20.
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.
肾纤维化是慢性肾脏病的一个致病因素，也是长期预后的一个重要预测指标。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，并研究了其在单侧输尿管梗阻（UUO）模型中减轻肾纤维化的能力。RB394 的疗效与 sEH 抑制剂（sEHi）、PPAR-γ 激动剂罗格列酮（Rosi）或它们的联合（sEHi + Rosi）进行了比较。所有干预治疗均在 UUO 诱导手术后 3 天开始通过饮用水给药，并持续 7 天。UUO 小鼠出现了胶原形成增加的肾纤维化，RB394 显著减轻了纤维化（P<0.05）。UUO 小鼠肾组织中α-平滑肌肌动蛋白（α-SMA）表达升高，除 sEHi 外，所有治疗均显著降低了肾组织中 α-SMA 的表达。UUO 小鼠肾纤维化和纤维化调节因子的 mRNA 表达升高，RB394 和 sEHi + Rosi 治疗降低了它们的表达。UUO 小鼠肾组织炎症明显，CD45 和 F4/80 阳性细胞浸润增加。RB394 和 sEHi + Rosi 治疗减轻了 UUO 小鼠的肾组织炎症。UUO 小鼠有肾小管和血管损伤。与 sEHi 或 Rosi 单一治疗相比，RB394 和 sEHi + Rosi 治疗更能减轻 UUO 小鼠的肾小管和血管损伤。与 UUO 小鼠相比，氧化应激标志物的肾组织 mRNA 表达显著升高（P<0.05）。与其他干预治疗相比，RB394 和 sEHi + Rosi 更能减轻氧化应激标志物的表达（P<0.05）。这些发现表明，RB394 通过减少肾组织炎症、氧化应激、肾小管损伤和血管损伤来减轻肾纤维化。总之，RB394 作为治疗肾纤维化和慢性肾脏病的一种有前途的治疗方法。
