Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
Mol Cell Biochem. 2011 Dec;358(1-2):287-95. doi: 10.1007/s11010-011-0979-y. Epub 2011 Jul 14.
Hypoxia-inducible factor-1 (HIF-1) could ameliorate renal ischemia reperfusion injury (IRI), but the underlying mechanism remains elusive. In the current study, we aim to investigate the possible role of prolyl hydroxylases inhibitor dimethyloxalylglycine (DMOG) in inducing delayed preconditioning-like effects against IRI. Mice were divided into four groups (n = 6): sham group; IRI group; DMOG group: pretreated with DMOG 24 h before IRI; and GW274150 + DMOG group: pretreated with DMOG followed by iNOS inhibitor GW274150 treatment 24 h before IRI. The results showed that the protein level of HIF-1a and the expression of its targets inducible nitric oxide synthase (iNOS), erythropoietin, and heme oxygenase-1 were obviously increased after administration of DMOG. Histological analysis of renal function showed improvement in tubulointerstitial injury due to ischemia by delayed preconditioning with DMOG. GW274150 antagonized the delayed renal protection afforded by DMOG as reflected by deteriorated renal dysfunction, aggravated histological injury, increased renal cell apoptosis, and increased vimentin expression in the kidney. In conclusion, our data demonstrate that DMOG pretreatment induces delayed renal protection against IRI in mice and the beneficial effects are mitigated by pharmacological inhibition of iNOS, suggesting that the protective effects derived from HIF-1 activation via DMOG in the kidney are partially mediated by iNOS.
缺氧诱导因子-1（HIF-1）可减轻肾缺血再灌注损伤（IRI），但其潜在机制尚不清楚。在本研究中，我们旨在研究脯氨酰羟化酶抑制剂二甲基草酰甘氨酸（DMOG）在诱导对 IRI 的延迟预处理样效应中的可能作用。将小鼠分为四组（n=6）：假手术组；IRI 组；DMOG 组：在 IRI 前 24 小时用 DMOG 预处理；GW274150+DMOG 组：在 IRI 前 24 小时用 DMOG 预处理，然后用 iNOS 抑制剂 GW274150 处理。结果表明，DMOG 给药后 HIF-1a 蛋白水平及其靶基因诱导型一氧化氮合酶（iNOS）、促红细胞生成素和血红素加氧酶-1的表达明显增加。肾功能组织学分析表明，DMOG 的延迟预处理可改善缺血引起的肾小管间质损伤。GW274150 拮抗了 DMOG 提供的延迟肾保护作用，表现为肾功能恶化、组织学损伤加重、肾细胞凋亡增加和肾脏中波形蛋白表达增加。总之，我们的数据表明，DMOG 预处理可诱导小鼠对 IRI 的延迟肾保护作用，而 iNOS 的药理学抑制可减轻其有益作用，表明 DMOG 通过 HIF-1 激活在肾脏中产生的保护作用部分是由 iNOS 介导的。
