Chinese PLA Institute of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College, 28 Fuxing Road, Beijing 100853, People's Republic of China.
J Am Soc Nephrol. 2011 Jul;22(7):1252-61. doi: 10.1681/ASN.2010040367. Epub 2011 Jun 30.
The molecular basis for aging of the kidney is not well understood. MicroRNAs (miRNAs) contribute to processes such as development, differentiation, and apoptosis, but their contribution to the aging process is unknown. Here, we analyzed the miRNA expression profile of young (3-month) and old (24-month) rat kidneys and identified the biologic pathways and genes regulated by differentially expressed miRNAs. We observed upregulation of 18 miRNAs with aging, mainly regulating the genes associated with energy metabolism, cell proliferation, antioxidative defense, and extracellular matrix degradation; in contrast, we observed downregulation of 7 miRNAs with aging, principally targeting the genes associated with the immune inflammatory response and cell-cycle arrest. Bioinformatics analysis suggested that superoxide dismutase 2 (SOD2) and thioredoxin reductase 2 (Txnrd2), located in the mitochondria, are potential targets of miR-335 and miR-34a, respectively. Aging mesangial cells exhibited significant upregulation of miR-335 and miR-34a and marked downregulation of SOD2 and Txnrd2. miR-335 and miR-34a inhibited expression of SOD2 and Txnrd2 by binding to the 3'-untranslated regions of each gene, respectively. Overexpression of miR-335 and miR-34a induced premature senescence of young mesangial cells via suppression of SOD2 and Txnrd2 with a concomitant increase in reactive oxygen species (ROS). Conversely, antisense miR-335 and miR-34a inhibited senescence of old mesangial cells via upregulation of SOD2 and Txnrd2 with a concomitant decrease in ROS. In conclusion, these results suggest that miRNAs may contribute to renal aging by inhibiting intracellular pathways such as those involving the mitochondrial antioxidative enzymes SOD2 and Txnrd2.
肾脏衰老的分子基础尚未完全阐明。微小 RNA（miRNA）在发育、分化和细胞凋亡等过程中发挥作用，但它们对衰老过程的贡献尚不清楚。在此，我们分析了年轻（3 个月）和年老（24 个月）大鼠肾脏的 miRNA 表达谱，确定了受差异表达 miRNA 调控的生物学途径和基因。我们观察到，随着年龄的增长，有 18 个 miRNA 上调，主要调控与能量代谢、细胞增殖、抗氧化防御和细胞外基质降解相关的基因；相反，我们观察到随着年龄的增长有 7 个 miRNA 下调，主要靶向与免疫炎症反应和细胞周期停滞相关的基因。生物信息学分析表明，超氧化物歧化酶 2（SOD2）和硫氧还蛋白还原酶 2（Txnrd2）位于线粒体，分别是 miR-335 和 miR-34a 的潜在靶点。衰老的肾小球系膜细胞表现出 miR-335 和 miR-34a 的显著上调，以及 SOD2 和 Txnrd2 的显著下调。miR-335 和 miR-34a 通过分别与每个基因的 3'-非翻译区结合，抑制 SOD2 和 Txnrd2 的表达。miR-335 和 miR-34a 的过表达通过抑制 SOD2 和 Txnrd2 诱导年轻系膜细胞发生早衰，同时伴随着活性氧（ROS）的增加。相反，反义 miR-335 和 miR-34a 通过上调 SOD2 和 Txnrd2 抑制老年系膜细胞衰老，同时伴随着 ROS 的减少。总之，这些结果表明，miRNA 可能通过抑制细胞内途径，如涉及线粒体抗氧化酶 SOD2 和 Txnrd2 的途径，从而促进肾脏衰老。
