Ichii Osamu, Otsuka-Kanazawa Saori, Horino Taro, Kimura Junpei, Nakamura Teppei, Matsumoto Manabu, Toi Makoto, Kon Yasuhiro
Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
PLoS One. 2014 Oct 17;9(10):e110383. doi: 10.1371/journal.pone.0110383. eCollection 2014.
MicroRNAs contribute to the pathogenesis of certain diseases and may serve as biomarkers. We analyzed glomerular microRNA expression in B6.MRLc1, which serve as a mouse model of autoimmune glomerulonephritis. We found that miR-26a was the most abundantly expressed microRNA in the glomerulus of normal C57BL/6 and that its glomerular expression in B6.MRLc1 was significantly lower than that in C57BL/6. In mouse kidneys, podocytes mainly expressed miR-26a, and glomerular miR-26a expression in B6.MRLc1 mice correlated negatively with the urinary albumin levels and podocyte-specific gene expression. Puromycin-induced injury of immortalized mouse podocytes decreased miR-26a expression, perturbed the actin cytoskeleton, and increased the release of exosomes containing miR-26a. Although miR-26a expression increased with differentiation of immortalized mouse podocytes, silencing miR-26a decreased the expression of genes associated with the podocyte differentiation and formation of the cytoskeleton. In particular, the levels of vimentin and actin significantly decreased. In patients with lupus nephritis and IgA nephropathy, glomerular miR-26a levels were significantly lower than those of healthy controls. In B6.MRLc1 and patients with lupus nephritis, miR-26a levels in urinary exosomes were significantly higher compared with those for the respective healthy control. These data indicate that miR-26a regulates podocyte differentiation and cytoskeletal integrity, and its altered levels in glomerulus and urine may serve as a marker of injured podocytes in autoimmune glomerulonephritis.
微小RNA参与某些疾病的发病机制，可能作为生物标志物。我们分析了B6.MRLc1小鼠肾小球微小RNA的表达，该小鼠作为自身免疫性肾小球肾炎的小鼠模型。我们发现，miR-26a是正常C57BL/6小鼠肾小球中表达最丰富的微小RNA，其在B6.MRLc1小鼠肾小球中的表达明显低于C57BL/6小鼠。在小鼠肾脏中，足细胞主要表达miR-26a，B6.MRLc1小鼠肾小球中miR-26a的表达与尿白蛋白水平和足细胞特异性基因表达呈负相关。嘌呤霉素诱导的永生化小鼠足细胞损伤降低了miR-26a的表达，扰乱了肌动蛋白细胞骨架，并增加了含有miR-26a的外泌体的释放。虽然miR-26a的表达随着永生化小鼠足细胞的分化而增加，但沉默miR-26a会降低与足细胞分化和细胞骨架形成相关基因的表达。特别是波形蛋白和肌动蛋白的水平显著降低。在狼疮性肾炎和IgA肾病患者中，肾小球miR-26a水平明显低于健康对照组。在B6.MRLc1小鼠和狼疮性肾炎患者中，尿外泌体中的miR-26a水平与各自的健康对照组相比显著更高。这些数据表明，miR-26a调节足细胞分化和细胞骨架完整性，其在肾小球和尿液中的水平改变可能作为自身免疫性肾小球肾炎中受损足细胞的标志物。
