Beijing Youan Hospital, Capital Medical University, Beijing, China.
Beijing Institute of Hepatology, Capital Medical University, Beijing, China.
J Cell Mol Med. 2019 Apr;23(4):2457-2467. doi: 10.1111/jcmm.14094. Epub 2019 Jan 23.
Acute kidney injury (AKI) has become a common disorder with a high risk of morbidity and mortality, which remains major medical problem without reliable and effective therapeutic intervention. Apoptosis-stimulating protein two of p53 (ASPP2) is a proapoptotic member that belongs to p53 binding protein family, which plays a key role in regulating apoptosis and cell growth. However, the role of ASPP2 in AKI has not been reported. To explore the role of ASPP2 in the progression of AKI, we prepared an AKI mouse model induced by ischaemia reperfusion (I/R) in wild-type (ASPP2 ) mice and ASPP2 haploinsufficient (ASPP2 ) mice. The expression profile of ASPP2 were examined in wild-type mice. The renal injury, inflammation response, cellular apoptosis and autophagic pathway was assessed in ASPP2 and ASPP2 mice. The renal injury, inflammation response and cellular apoptosis was analysed in ASPP2 and ASPP2 mice treated with 3-methyladenine or vehicle. The expression profile of ASPP2 showed an increase at the early stage while a decrease at the late stage during renal injury. Compared with ASPP2 mice, ASPP2 deficiency protected mice against renal injury induced by I/R, which mainly exhibited in slighter histologic changes, lower levels of blood urea nitrogen and serum creatinine, and less apoptosis as well as inflammatory response. Furthermore, ASPP2 deficiency enhanced autophagic activity reflecting in the light chain 3-II conversion and p62 degradation, while the inhibition of autophagy reversed the protective effect of ASPP2 deficiency on AKI. These data suggest that downregulation of ASPP2 can ameliorate AKI induced by I/R through activating autophagy, which may provide a novel therapeutic strage for AKI.
急性肾损伤（AKI）已成为一种常见的高发病率和死亡率疾病，仍然是一个重大的医学问题，缺乏可靠和有效的治疗干预措施。p53 结合蛋白家族中的凋亡刺激蛋白 2（ASPP2）是一种促凋亡成员，在调节细胞凋亡和细胞生长中发挥着关键作用。然而，ASPP2 在 AKI 中的作用尚未报道。为了探讨 ASPP2 在 AKI 进展中的作用，我们在野生型（ASPP2）和 ASPP2 杂合子（ASPP2）小鼠中制备了缺血再灌注（I/R）诱导的 AKI 小鼠模型。在野生型小鼠中检测了 ASPP2 的表达谱。在 ASPP2 和 ASPP2 小鼠中评估了肾损伤、炎症反应、细胞凋亡和自噬途径。在 ASPP2 和 ASPP2 小鼠中用 3-甲基腺嘌呤或载体处理后分析了肾损伤、炎症反应和细胞凋亡。ASPP2 的表达谱显示在肾损伤早期增加，而在晚期减少。与 ASPP2 小鼠相比，ASPP2 缺失可防止 I/R 诱导的肾损伤，主要表现为组织学变化较轻，血尿素氮和血清肌酐水平较低，凋亡和炎症反应较少。此外，ASPP2 缺失增强了自噬活性，反映在 LC3-II 转换和 p62 降解增加，而自噬抑制逆转了 ASPP2 缺失对 AKI 的保护作用。这些数据表明，下调 ASPP2 通过激活自噬可以改善 I/R 诱导的 AKI，这可能为 AKI 提供一种新的治疗策略。
