Ma Ming, Fu Lei, Jia Zihao, Zhong Qiang, Huang Zhongli, Wang Xianding, Fan Yu, Lin Tao, Song Turun
Urology Department, West China Hospital, Sichuan University, Chengdu, China.
Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
Ann Transl Med. 2021 Oct;9(20):1545. doi: 10.21037/atm-21-4678.
Kidney ischemia-reperfusion (I/R) injury is an independent risk factor for delayed graft function after kidney transplantation with long-term graft survival deterioration. Previously, we found that the upregulated expression of miR-17-5p exerts a protective effect in kidney I/R injury, but the mechanism has not been clearly studied.
A kidney I/R injury model was induced in adult C57BL/6 male mice (20-22 g) by clamping both kidney pedicles for 30 min. The miR-17-5p agomir complex was injected into mice 24 h before surgery via the tail vein at a total injection volume of 10 µL/g body weight. The mice were euthanized on post-I/R injury day 2, and kidney function, apoptosis, autophagy, and related molecules were then detected. Human kidney-2 (HK-2) cells, which underwent hypoxia/reoxygenation, were treated with the miR-17-5p agomir, miR-17-5p antagomir, and small interfering ribonucleic acids (siRNAs). Cell viability, apoptosis, autophagy, and molecules were also examined.
Autophagy, miR-17-5p expression, and kidney function damage were significantly more increased in the I/R group than in the sham group. In the cultured HK-2 cells underwent hypoxia/reoxygenation, the miR-17-5p agomir directly inhibited the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Bcl-2 like protein 11 (BIM), and attenuated apoptosis and autophagy. Further, miR-17-5p inhibited autophagy by activating the protein kinase B (Akt)/Beclin1 pathway, which was suppressed by siRNAs. Additionally, the administration of miR-17-5p agomir greatly improved kidney function in the I/R mice group by inhibiting autophagy and apoptosis.
These findings suggest a new possible therapeutic strategy for the prevention and treatment of kidney I/R injury. The upregulation of miR-17-5p expression appears to inhibit apoptosis and autophagy by suppressing PTEN and BIM expression, which in turn upregulates downstream Akt/Beclin1 expression.
肾缺血再灌注（I/R）损伤是肾移植后移植肾功能延迟恢复及长期移植肾存活恶化的独立危险因素。此前，我们发现miR-17-5p表达上调在肾I/R损伤中发挥保护作用，但其机制尚未明确研究。
通过夹闭成年C57BL/6雄性小鼠（20-22 g）双侧肾蒂30分钟诱导肾I/R损伤模型。手术前24小时经尾静脉将miR-17-5p agomir复合物以10 μL/g体重的总注射体积注入小鼠体内。在I/R损伤后第2天对小鼠实施安乐死，然后检测肾功能、细胞凋亡、自噬及相关分子。对经历缺氧/复氧的人肾-2（HK-2）细胞用miR-17-5p agomir、miR-17-5p antagomir和小干扰核糖核酸（siRNA）进行处理。同时检测细胞活力、细胞凋亡、自噬及相关分子。
与假手术组相比，I/R组自噬、miR-17-5p表达及肾功能损害显著增加。在经历缺氧/复氧的培养HK-2细胞中，miR-17-5p agomir直接抑制第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）及Bcl-2样蛋白11（BIM）的表达，并减轻细胞凋亡和自噬。此外，miR-17-5p通过激活蛋白激酶B（Akt）/Beclin1通路抑制自噬，而该通路被siRNA抑制。另外，给予miR-17-5p agomir可通过抑制自噬和细胞凋亡显著改善I/R小鼠组的肾功能。
这些发现提示了一种预防和治疗肾I/R损伤的新的可能治疗策略。miR-17-5p表达上调似乎通过抑制PTEN和BIM表达来抑制细胞凋亡和自噬，进而上调下游Akt/Beclin1表达。
