title: miR-335 and miR-34a Promote renal senescence by suppressing mitochondrial antioxidative enzymes.
abstract: 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.
authors: Chinese PLA Institute of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College, 28 Fuxing Road, Beijing 100853, People's Republic of China.
authors: Xue-Yuan
authors: XY
authors: Bai
authors: Yuxiang
authors: Y
authors: Ma
authors: Rui
authors: R
authors: Ding
authors: Bo
authors: B
authors: Fu
authors: Suozhu
authors: S
authors: Shi
authors: Xiang-Mei
authors: XM
authors: Chen
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015536:Down-Regulation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D018384:Oxidative Stress; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D054482:Thioredoxin Reductase 2 / Q000235:genetics / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D035683:MicroRNAs; D013482:Superoxide Dismutase; D054482:Thioredoxin Reductase 2; D000099156:Superoxide Dismutase 2; C560944:MIRN34 microRNA, rat; C516129:Txnrd2 protein, rat