The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Eur J Pharmacol. 2013 Apr 5;705(1-3):11-9. doi: 10.1016/j.ejphar.2013.02.028. Epub 2013 Feb 27.
Acute kidney injury (AKI) is a common problem characterized by an inflammatory response in the kidney and oxidative stress. However, there are no interventions to prevent AKI. Glutamine is an important precursor of glutathione and has also been shown to induce heat shock proteins (HSP). Thus, glutamine may affect both oxidative stress and inflammation. This study was to explore the effects of glutamine pretreatment on nephrotoxic AKI and to investigate the underlying mechanisms. First, the effects of alternate doses of glutamine were compared in CD-1 mice with AKI induced with folic acid intra-peritoneal injection. Then the effects of glutamine quercetin (an HSP inhibitor), and quercetin+glutamine, were compared in the same AKI model. AKI were assessed with plasma creatinine, urine neutrophil gelatinase-associated lipocalin, and renal histology. Inflammatory response was monitored with renal tumor necrosis factor (TNF-α), chemkines (CXCL1 and CCL2) contents, and neutrophil infiltration. Oxidative injury was detected with reduced glutathione, malondialdehyde, and protein thiol. Glutamine provided dose-dependent renal protection. Pretreatment with quercetin, which was showed to inhibit HSP-70 expression, abolished glutamine's renal-protective effects. Quercetin also abrogated glutamine's beneficial effects on renal TNF-α, chemokines, and neutrophil infiltration. However, quercetin did not affect glutamine's anti-oxidative effects. These results suggest that glutamine's renal-protective effects are mainly related to its activation of HSP-70, which mitigates inflammatory response, renal neutrophil infiltration and subsequent AKI. Regulating neutrophil infiltration might be a potential therapeutic target for AKI.
急性肾损伤 (AKI) 是一种常见的疾病，其特征为肾脏的炎症反应和氧化应激。然而，目前尚无预防 AKI 的干预措施。谷氨酰胺是谷胱甘肽的重要前体，也已被证明可诱导热休克蛋白 (HSP)。因此，谷氨酰胺可能同时影响氧化应激和炎症。本研究旨在探讨谷氨酰胺预处理对肾毒性 AKI 的影响，并探讨其潜在机制。首先，在经腹腔注射叶酸诱导 AKI 的 CD-1 小鼠中比较了不同剂量谷氨酰胺的作用。然后，在相同的 AKI 模型中比较了谷氨酰胺槲皮素（HSP 抑制剂）和槲皮素+谷氨酰胺的作用。AKI 采用血浆肌酐、尿中性粒细胞明胶酶相关脂质运载蛋白和肾组织学进行评估。炎症反应通过肾肿瘤坏死因子 (TNF-α)、趋化因子 (CXCL1 和 CCL2) 含量和中性粒细胞浸润进行监测。氧化损伤通过还原型谷胱甘肽、丙二醛和蛋白质巯基检测。谷氨酰胺提供了剂量依赖性的肾脏保护作用。预先给予槲皮素（显示可抑制 HSP-70 表达），则消除了谷氨酰胺的肾脏保护作用。槲皮素还消除了谷氨酰胺对肾脏 TNF-α、趋化因子和中性粒细胞浸润的有益作用。然而，槲皮素并未影响谷氨酰胺的抗氧化作用。这些结果表明，谷氨酰胺的肾脏保护作用主要与其激活 HSP-70 有关，这可减轻炎症反应、肾脏中性粒细胞浸润和随后的 AKI。调节中性粒细胞浸润可能是 AKI 的一个潜在治疗靶点。
