Department of Oral Biology, Georgia Regents University, Augusta, GA, USA.
Clin Sci (Lond). 2013 Oct;125(7):349-59. doi: 10.1042/CS20130003.
We have shown previously that inhibition of sEH (soluble epoxide hydrolase) increased EETs (epoxyeicosatrienoic acids) levels and reduced renal injury in diabetic mice and these changes were associated with induction of HO (haem oxygenase)-1. The present study determines whether the inhibition of HO negates the renoprotective effect of sEH inhibition in diabetic SHR (spontaneously hypertensive rats). After 6 weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor t-AUCB {trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid}, treated with the HO inhibitor SnMP (stannous mesoporphyrin), and treated with both inhibitors for 4 more weeks; non-diabetic SHR served as a control group. Induction of diabetes significantly increased renal sEH expression and decreased the renal EETs/DHETEs (dihydroxyeicosatrienoic acid) ratio without affecting HO-1 activity or expression in SHR. Inhibition of sEH with t-AUCB increased the renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR; however, it did not significantly alter systolic blood pressure. Treatment of diabetic SHR with t-AUCB significantly reduced the elevation in urinary albumin and nephrin excretion, whereas co-administration of the HO inhibitor SnMP with t-AUCB prevented these changes. Immunohistochemical analysis revealed elevations in renal fibrosis as indicated by increased renal TGF-β (transforming growth factor β) levels and fibronectin expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with t-AUCB prevented its ability to reduce renal fibrosis in diabetic SHR. In addition, SnMP treatment also prevented t-AUCB-induced decreases in renal macrophage infiltration, IL-17 expression and MCP-1 levels in diabetic SHR. These findings suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.
我们之前已经表明，抑制 sEH（可溶性环氧化物水解酶）可增加 EETs（环氧二十碳三烯酸）水平并减少糖尿病小鼠的肾损伤，这些变化与 HO-1（血红素加氧酶-1）的诱导有关。本研究旨在确定抑制 HO 是否会消除 sEH 抑制在糖尿病 SHR（自发性高血压大鼠）中的肾脏保护作用。在链脲佐菌素诱导糖尿病 6 周后，SHR 被分为以下几组：未治疗组、用 sEH 抑制剂 t-AUCB（反式-4-[4-（3-金刚烷-1-基-脲基）环己氧基]-苯甲酸）治疗组、用 HO 抑制剂 SnMP（锡原卟啉）治疗组以及再用两种抑制剂治疗 4 周的治疗组；非糖尿病 SHR 作为对照组。糖尿病诱导显著增加了 SHR 肾脏 sEH 的表达，并降低了肾脏 EETs/DHETEs（二羟二十碳三烯酸）的比值，而不影响 HO-1 活性或表达。t-AUCB 抑制 sEH 增加了糖尿病 SHR 肾脏的 EETs/DHETEs 比值和 HO-1 活性；然而，它并未显著改变收缩压。用 t-AUCB 治疗糖尿病 SHR 可显著降低尿白蛋白和肾素排泄的升高，而用 HO 抑制剂 SnMP 与 t-AUCB 共同给药则可防止这些变化。免疫组织化学分析显示，糖尿病 SHR 中 TGF-β（转化生长因子-β）水平和纤维连接蛋白表达的升高表明肾脏纤维化增加，这些变化在 sEH 抑制后减少。用 SnMP 与 t-AUCB 共同给药可防止其降低糖尿病 SHR 肾脏纤维化的能力。此外，SnMP 治疗还可防止 t-AUCB 诱导的糖尿病 SHR 肾巨噬细胞浸润、IL-17 表达和 MCP-1 水平降低。这些发现表明，HO-1 诱导参与了 sEH 抑制对糖尿病肾损伤的保护作用。
