肢体缺血预适应保护顺铂诱导AKI的新机制：miR-144调控PI3K/Akt/GSK3β通路

Acute kidney injury (AKI) is a common clinical critical disease. There is still no effective prophylactic and therapeutic measures. Limb ischemic preconditioning (LIPC) is a non-invasive, safe, effective, feasible and cost-effective method to protect against various organs injury. The applicant found LIPC protected the kidney via the PI3K/Akt/GSK3β pathway in the previous experiment. Our recent preliminary experiments revealed that LIPC induced significantly high expressions of pri-miR-144 in the gastrocnemius muscle of the limb performed LIPC and miR-144 in kidney tissue. Therefore, we speculate that LIPC increases the expression of pri-miR-144 in the limb, followed by the high expression of miR-144 in kidney tissue, and miR-144 protects the kidney via the PI3K/Akt/GSK3β signaling pathway regulated by the target gene of miR-144 (PTEN). We will explore the renoprotection of miR-144 against AKI, especially where miR-144 is from and how miR-144 regulates the PI3K/Akt/GSK3β pathway using bioinformatics, miRNA technologies and RNA transfection methods in AKI animal models and cells injury models induced by cisplatin. This study may provide new mechanisms for LIPC protecting against AKI.

急性肾损伤（AKI）是临床常见危重症，目前仍无有效的防治措施。肢体缺血预适应 (LIPC)是一种能够对抗各种损伤以保护器官的方法，具有无创、安全、有效、经济实用的特点。申请人前期工作发现：LIPC通过PI3K/Akt/GSK3β通路保护肾脏，近期预实验结果显示：LIPC诱导预缺血肢体腓肠肌pri-miR-144和肾组织miR-144表达明显增高。因而推测LIPC诱导肢体产生pri-miR-144，从而肾组织miR-144表达增多，通过靶基因PTEN调控PI3K/Akt/GSK3β信号通路，进而发挥肾保护作用。本研究拟利用生物信息学、miRNA相关技术及RNA转染等方法，通过顺铂诱导AKI动物模型和细胞损伤模型，探讨miR-144在预防AKI发生中的作用，特别是miR-144的来源以及对PI3K/Akt/GSK3β通路的调控作用，以阐明LIPC预防AKI的新机制。

急性肾损伤（AKI）是临床常见危重症，目前仍无有效的防治措施。肢体缺血预适应(LIPC)是一种能够对抗各种损伤以保护器官的方法，具有无创、安全、有效、经济实用的特点。利用生物信息学、miRNA相关技术及RNA转染等方法，通过顺铂诱导AKI动物模型和细胞损伤模型，研究miR-144在预防AKI发生中的作用，特别是miR-144的来源以及对PI3K/Akt/GSK3β通路的调控作用。研究结果显示:LIPC 对顺铂诱导AKI小鼠肾脏有保护作用,LIPC 诱导肾组织miR-144表达增多,miR-144通过调控PTEN,间接影响PI3K/Akt/GSK3β通路减轻顺铂诱导炎症反应、氧化应激反应、线粒体肿胀和膜电位下降以及肾脏病理损伤等。采用荧光素酶报告基因检测技术验证了PTEN为miR-144 靶基因。miR-144可能来源于LIPC诱导肢体pri-miR-144,进而剪切成pre-miR-144和miR-144，由exosome作为载体，经血液循环到达肾脏后，释放pre-miR-144和/或miR-144,致肾组织miR-144表达增多。该研究不仅拓展了LIPC作为潜在的器官保护方法在防治急性肾损伤中的研究，也为以miR-144和PI3K/Akt/GSK3β为靶点干预顺铂所致AKI提供理论依据，从而为AKI的防治提供新的思路和手段。