Xiao Xiangcheng, Tang Rong, Zhou Xiao, Peng Ling, Yu Pingping
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
The Nephrotic Laboratory of Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Exp Ther Med. 2016 Aug;12(2):915-924. doi: 10.3892/etm.2016.3443. Epub 2016 Jun 8.
Acute kidney injury (AKI) is characterized by an acute reduction in kidney function as identified by an increase in serum creatinine levels and reduction in urine output. Kidney injury molecule-1 (Kim-1) is a hallmark of kidney diseases, since it is typically non-detectable in the non-injured kidney, but upregulated and excreted in the urine during AKI. Aldosterone (Aldo) is a mediator of the renin-angiotensin-Aldo system with a pivotal role in the regulation of salt and extracellular fluid metabolism. In the present study, mice subjected to renal ischemia/reperfusion-induced AKI were investigated. The mice exhibited elevated levels of Aldo and angiotensin II, together with increased Kim-1 expression levels in renal tissue. Treatment of the mice with the Aldo receptor antagonist spironolactone decreased Kim-1 expression levels. These results suggest that Aldo may be associated with the expression of Kim-1 during AKI. However, the molecular mechanism underlying the role of Aldo in Kim-1 expression is unclear, and thus was investigated using NRK-52E cells. Aldo was found to induce the apoptosis of NRK-52E cells via the hypermethylation of rno-microRNA (miR)-203 and upregulation of Kim-1. In addition, luciferase reporter assays demonstrated that Kim-1 was a target gene of rno-miR-203 in NRK-52E cells. Furthermore, Aldo-induced NRK-52E cell apoptosis was reduced by treatment with pre-miR-203 and spironolactone to a greater extent when compared with either alone. The results may provide a promising diagnostic marker or novel therapeutic target for AKI.
急性肾损伤（AKI）的特征是肾功能急剧下降，表现为血清肌酐水平升高和尿量减少。肾损伤分子-1（Kim-1）是肾脏疾病的一个标志，因为在未受损的肾脏中通常检测不到它，但在AKI期间会在尿液中上调并排出。醛固酮（Aldo）是肾素-血管紧张素-醛固酮系统的介质，在盐和细胞外液代谢调节中起关键作用。在本研究中，对遭受肾缺血/再灌注诱导的AKI的小鼠进行了研究。这些小鼠的醛固酮和血管紧张素II水平升高，同时肾组织中Kim-1表达水平增加。用醛固酮受体拮抗剂螺内酯治疗小鼠可降低Kim-1表达水平。这些结果表明，醛固酮可能与AKI期间Kim-1的表达有关。然而，醛固酮在Kim-1表达中作用的分子机制尚不清楚，因此使用NRK-52E细胞进行了研究。发现醛固酮通过rno-微小RNA（miR）-203的高甲基化和Kim-1的上调诱导NRK-52E细胞凋亡。此外，荧光素酶报告基因检测表明，Kim-1是NRK-52E细胞中rno-miR-203的靶基因。此外，与单独使用相比，用pre-miR-203和螺内酯治疗可更大程度地减少醛固酮诱导的NRK-52E细胞凋亡。这些结果可能为AKI提供一个有前景的诊断标志物或新的治疗靶点。
