预防性抑制可溶性环氧化物水解酶可延迟新西兰黑/白 F1 小鼠肾炎的发病并改善肾脏损伤。

Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice.

机构信息

Department of Nephrology and Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.

Department of Entomology and Nematology and Comprehensive Cancer Center, UC Davis, California, USA.

出版信息

Sci Rep. 2019 Jun 20;9(1):8993. doi: 10.1038/s41598-019-45299-5.

Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease.

环氧脂肪酸（EpFAs）是细胞色素 P450 依赖的花生四烯酸衍生物，具有抗炎特性，但它们对系统性红斑狼疮（SLE）等自身免疫性疾病的影响尚未得到研究。我们通过药理学抑制可溶性环氧化物水解酶（sEH，EPHX2）来评估 EpFAs 及其代谢物在狼疮易感 NZB/W F1 小鼠中的影响。在狼疮易感的 NZB/W F1 小鼠中，以预防和治疗的方式给予 sEH 抑制剂 1770。sEH 的预防性抑制可显著提高存活率并减少蛋白尿。相比之下，sEH 抑制剂治疗的肾炎小鼠没有生存获益；然而，与对照组相比，其组织学变化减少。在人类中，与 10 名健康对照者相比，47 名 SLE 患者的尿 EpFA 水平有显著差异。NZB/W F1 小鼠和狼疮肾炎（LN）患者的肾脏 EPHX2 基因表达均显著降低。EpFAs 与 SLE 疾病活动度的相关性以及 LN 中肾脏 EPHX 基因表达的降低表明这些成分在人类疾病中具有作用。