MicroRNA-150 deletion in mice protects kidney from myocardial infarction-induced acute kidney injury
MicroRNA-150 deletion in mice protects kidney from myocardial infarction-induced acute kidney injury
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DOI：
10.1152/ajprenal.00076.2015
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发表时间：
2015-09-15
影响因子：
4.2
通讯作者：
Ramesh, Ganesan
中科院分区：
文献类型：
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作者：
Ranganathan, Punithavathi;Jayakumar, Calpurnia;Ramesh, Ganesan
尽管在动物模型中对急性肾损伤（阿基）有了更多的了解，但许多临床前研究都无法翻译。大部分数据来自双侧肾蒂夹闭模型与热缺血。然而，人类肾脏的缺血性损伤明显不同，并且不涉及肾血管的夹紧。使用冠状动脉左前降支模型的永久结扎来测试微小RNA（miR）-150在阿基中的作用。该模型中的心肌梗死导致阿基，这与人类心脏搭桥手术相似。此外，血清肌酐和生物标志物升高的时间过程也与人类缺血性损伤相似。miR-150的缺失抑制了阿基，这与抑制炎症和间质细胞凋亡有关。内皮细胞标记物和凋亡标记物的免疫荧光染色表明，在该模型中，死亡细胞主要是内皮细胞，上皮细胞凋亡最少。有趣的是，miR-150的缺失也抑制了间质纤维化。与保护作用一致，miR-150缺失导致其靶基因胰岛素样生长因子-1受体（IGF-1 R）的诱导和miR-150在内皮细胞中的过表达下调IGF-1 R，表明miR-150可能通过抑制IGF-1 R途径介导其有害作用。
Despite greater understanding of acute kidney injury (AKI) in animal models, many of the preclinical studies are not translatable. Most of the data were derived from a bilateral renal pedicle clamping model with warm ischemia. However, ischemic injury of the kidney in humans is distinctly different and does not involve clamping of renal vessel. Permanent ligation of the left anterior descending coronary artery model was used to test the role of microRNA (miR)-150 in AKI. Myocardial infarction in this model causes AKI which is similar to human cardiac bypass surgery. Moreover, the time course of serum creatinine and biomarker elevation were also similar to human ischemic injury. Deletion of miR-150 suppressed AKI which was associated with suppression of inflammation and interstitial cell apoptosis. Immunofluorescence staining with endothelial marker and marker of apoptosis suggested that dying cells are mostly endothelial cells with minimal epithelial cell apoptosis in this model. Interestingly, deletion of miR-150 also suppressed interstitial fibrosis. Consistent with protection, miR-150 deletion causes induction of its target gene insulinlike growth factor-1 receptor (IGF-1R) and overexpression of miR-150 in endothelial cells downregulated IGF-1R, suggesting miR-150 may mediate its detrimental effects through suppression of IGF-1R pathways.