Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways
Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways
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DOI：
10.1172/jci75852
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发表时间：
2015-01-01
影响因子：
15.9
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
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作者：
Gomez, Ivan G.;MacKenna, Deidre A.;Duffield, Jeremy S.
microRNA-21（miR-21）可能通过沉默对细胞ATP产生、ROS产生和炎症信号传导至关重要的代谢途径，促进包括肾脏在内的多个器官中纤维化疾病的发病机制。在这里，我们开发了高度特异性的寡核苷酸，当皮下给药时，它们分布到肾脏并抑制miR-21功能，并评估了这些抗miR-21寡核苷酸在慢性肾脏疾病中的治疗潜力。在Alport肾病的小鼠模型中，与溶剂处理的小鼠相比，miR-21沉默未产生任何不良影响，并导致显著较轻的肾脏疾病，具有最小的白蛋白尿和功能障碍。miR-21沉默显著改善了Alport小鼠的存活率，并降低了组织学终点，包括肾小球硬化、间质纤维化、肾小管损伤和炎症。抗miR-21增强了肾小球、肾小管和间质细胞中的PPAR α/维甲酸X受体（PPAR α/RXR）活性和下游信号通路。此外，miR-21沉默增强了线粒体功能，这减少了线粒体！ROS的产生，从而保留了肾小管功能。抑制miR-21可保护肾小球和间质细胞免受TGF-β诱导的纤维化和炎症，这可能是由于增强的PPAR α/RXR活性和改善的线粒体功能。总之，这些结果表明，抑制miR-21代表了慢性肾脏疾病（包括Alport肾病）的潜在治疗策略。
MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti-miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti-miR-21 enhanced PPAR alpha/retinoid X receptor (PPAR alpha/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondria! ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-beta-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPAR alpha/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy.