MicroRNA-21 (miR-21) was identified as a hypomethylated gene locus in kidney cancers and as a robustly upregulated miRNA in human acute and chronic kidney diseases. Mutational and bioinformatic analysis in mice identified about 100 gene targets for miR-21 in the kidney, which are highly enriched for metabolic and mitochondrial functions. miR-21 deficient mice are protected from epithelial injury and fibrosis in disease settings [1Chau B.N., Xin C., Hartner J., Ren S., Castano A.P., Linn G., et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways Sci Transl Med 2012 ;  4 (121) : 121ra1810.1126/scitranslmed.3003205

Cliquez ici pour aller à la section Références]. In vitro analysis of miR-21 function indicates it is upregulated by stress in epithelium, podocytes and fibroblasts, suppresses mitochondrial biogenesis, mitochondrial functions and triggers high levels of mitochondrial ROS generation, thereby amplifying injury responses in the epithelium and promoting a fibrogenic phenotype in fibroblasts and podocytes (Figure 1). A major target for miR-21 is the transcription factor, peroxisome proliferator activated receptor-α (PPARα), which transcriptionally regulates mitochondrial biogenesis, but also has direct anti-inflammatory effects. We developed a novel oligonucleotide anti-miRNA against miR-21 with excellent drug-like properties, demonstrated that it recapitulates miR-21 deficiency, and studied its function in several animal models of kidney disease. In mice with Alport nephropathy, subcutaneous delivery of anti-miR21 oligonucleotides prevents organ failure and improves longevity by 50% [2Gomez I.G., MacKenna D.A., Johnson B.G., Kaimal V., Roach A.M., Ren S., et al. Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways J Clin Invest 2015 ;  125 (1) : 141-15610.1172/JCI75852Epub 2014 Nov 21.  [cross-ref]

Cliquez ici pour aller à la section Références]. We conclude that using anti-miR21 to suppress miR21 functions, improves epithelial function, reduces fibrogenesis and enhances survival in models of kidney disease, and is a promising new therapeutic for human kidney diseases.