MicroRNAs (miRs) provide fine-tuning of gene expression via inhibition of translation. MiR-451 has a modulatory role in cell cycling via down-regulation of the mechanistic target of rapamycin (mTOR). We aimed to test whether chronic, systemic inhibition of miR-451 would enhance renal fibrosis (associated with deranged autophagy). Adult, TallyHo/Jng mice (obese, insulin-resistant) were randomized to two treatment groups to receive either miR-451 inhibition (via a locked nucleic acid, LNA, construct) or a similar scrambled-LNA control for 8 weeks. All mice were fed a high-fat diet (60% kcal from fat) ad libitum and humanely euthanized after 12 weeks. Kidneys and blood were collected for analysis. Renal expression of miR-451 was 6-fold lower in inhibitor-treated mice, compared to control mice. MiR-451 inhibition increased kidney weight, collagen, and glycogen deposition. Blood chemistry revealed significantly higher Na⁺ and anion gap (relative metabolic acidosis) in inhibitor-treated mice. Western blotting and immunohistochemistry of kidney revealed that the inhibitor increased markers of renal injury and fibrosis, e.g., kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL), transforming growth factor beta (TGF-ß), 14-3-3 protein zeta (YWHAZ, 14-3-3ζ), mechanistic target of rapamycin (mTOR), adenosine, monophosphate kinase a (AMPKa), calcium-binding protein 39 (CAB39), matrix metallopeptidase-9 (MMP-9), and the autophagy receptor sequestosome 1 (SQSTM1/p62). In contrast, the inhibitor reduced the epithelial cell integrity marker, type IV collagen (COLIV), and autophagy markers, microtubule-associated protein 1A/1B light chain 3B (LC3-II), and beclin1 (BECN1). Taken together these results support a protective role for miR-451 in reducing renal fibrosis by enhancing autophagy in obese mice.

中文翻译：

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在 Tallyho/Jng 小鼠中，miR-451 的系统性抑制会增加纤维化信号并减少自噬反应以加剧肾损伤。

MicroRNA (miR) 通过抑制翻译提供基因表达的微调。MiR-451 通过下调雷帕霉素 (mTOR) 的机制靶点在细胞周期中发挥调节作用。我们的目的是测试 miR-451 的慢性、全身性抑制是否会增强肾纤维化（与紊乱的自噬相关）。成年 TallyHo/Jng 小鼠（肥胖、胰岛素抵抗）被随机分配到两个治疗组，接受 miR-451 抑制（通过锁定核酸、LNA、构建体）或类似的乱序 LNA 对照，持续 8 周。所有小鼠都被随意喂食高脂肪饮食（60% kcal 来自脂肪），并在 12 周后被人道地安乐死。收集肾脏和血液用于分析。与对照小鼠相比，miR-451 的肾脏表达在抑制剂处理的小鼠中低 6 倍。MiR-451 抑制增加肾脏重量、胶原蛋白、和糖原沉积。血液化学显示 Na 显着升高⁺和抑制剂治疗小鼠的阴离子间隙（相对代谢性酸中毒）。肾脏的蛋白质印迹和免疫组织化学显示抑制剂增加了肾损伤和纤维化的标志物，例如肾损伤分子 1 (KIM1) 和中性粒细胞明胶酶相关载脂蛋白 (NGAL)、转化生长因子 β (TGF-ß)、14-3 -3 zeta 蛋白 (YWHAZ, 14-3-3ζ)、雷帕霉素 (mTOR) 的机制靶标、腺苷、单磷酸激酶 a (AMPKa)、钙结合蛋白 39 (CAB39)、基质金属肽酶 9 (MMP-9)、和自噬受体 sequestosome 1 (SQSTM1/p62)。相反，抑制剂减少了上皮细胞完整性标记物、IV 型胶原蛋白 (COLIV) 和自噬标记物、微管相关蛋白 1A/1B 轻链 3B (LC3-II) 和 beclin1 (BECN1)。