Roche Clothilde, Guerrot Dominique, Harouki Najah, Duflot Thomas, Besnier Marie, Rémy-Jouet Isabelle, Renet Sylvanie, Dumesnil Anaïs, Lejeune Annie, Morisseau Christophe, Richard Vincent, Bellien Jeremy
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Nephrology, Rouen University Hospital, Rouen, France.
Prostaglandins Other Lipid Mediat. 2015 Jul;120:148-54. doi: 10.1016/j.prostaglandins.2015.04.011. Epub 2015 May 27.
This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFκB inhibitor Iκ≡ and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal inflammation in overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of diabetic nephropathy.
抑制环氧二十碳三烯酸（EETs）降解酶可溶性环氧化物水解酶可在糖尿病肾病早期提供肾脏保护作用。将可溶性环氧化物水解酶（sEH）抑制剂t - AUCB（饮用水中浓度为10mg/l）与磺酰脲类药物格列本脲（80mg/l）对肾脏的作用进行比较，二者均在接受16周高脂饮食（HFD，脂肪含量60%）的FVB小鼠中给药8周。喂食对照普通饲料（脂肪含量10%）的小鼠和未接受治疗的HFD小鼠作为对照。与未接受治疗的HFD小鼠相比，用t - AUCB治疗的HFD小鼠EET降解减少，表现为血浆EETs与二羟环氧二十碳三烯酸（DHETs）的比值升高；EET生成增加，表现为EETs + DHETs水平升高，这与细胞色素P450环氧化酶表达的诱导有关。两种药物均同样降低空腹血糖，但只有t - AUCB可防止HFD小鼠尿白蛋白与肌酐比值升高。组织病理学分析表明，t - AUCB减轻了肾脏炎症，这与核因子κB（NFκB）抑制剂IκB的mRNA表达增加以及单核细胞趋化蛋白-1（MCP - 1）、环氧化酶2（COX2）和血管细胞黏附分子-1（VCAM - 1）表达的相应降低有关。最后，HFD小鼠中活性氧生成略有显著增加，同时烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（NOX2）表达增强。两种药物均未改变这些参数，但t - AUCB增加了抗氧化酶超氧化物歧化酶1的表达。这些结果表明，独立于其降糖作用之外，抑制sEH可预防超重高血糖小鼠的微量白蛋白尿和肾脏炎症，提示该药理学策略可能对糖尿病肾病的治疗有用。
