Research ArticleFibrosis

MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways

Science Translational Medicine  15 Feb 2012:
Vol. 4, Issue 121, pp. 121ra18
DOI: 10.1126/scitranslmed.3003205

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Defeating Fibrosis

Although small—just 22 nucleotides in length—microRNA-21 (miR-21) packs a mighty punch, posttranscriptionally regulating the expression of many genes. Furthermore, miR-21 dysregulation has been linked to cardiac disease and cancer. Now, Chau et al. show that dysregulated miR-21 also contributes to kidney fibrosis, an inappropriate wound-healing response that promotes organ failure.

The authors first identified miRNAs that were up-regulated in two mouse models of kidney injury. On the basis of preliminary analyses, Chau et al. focused on miR-21. In mice, miR-21 is up-regulated in the kidney soon after injury, before fibrosis appears. Moreover, miR-21 is up-regulated in human kidneys from patients with problems such as acute kidney injury. Although mice that lack miR-21 are healthy and display relatively normal gene expression in the kidney, after injury, a derepressed set of miR-21 target mRNAs becomes apparent, and they develop much less fibrosis than their littermates that express miR-21. In normal mice, inhibition of miR-21 with complementary oligonucleotides likewise reduces kidney fibrosis after injury. To understand how miR-21 amplifies kidney fibrosis, the authors examined kidney gene expression profiles in mice with and without miR-21 after kidney injury. About 700 genes were derepressed in kidneys from mice without miR-21; surprisingly, genes involved in metabolic pathways—particularly involving fatty acid and lipid oxidation—were among the up-regulated genes, whereas those involved in immune or cell proliferation pathways were not. One derepressed gene, encoding peroxisome proliferator–activated receptor α (PPARα), a regulator of lipid metabolism, is a direct target of miR-21. Overexpression of PPARα in the kidney during injury inhibited fibrosis in mice; conversely, in mice that lacked PPARα, inhibition of miR-21 no longer protected against kidney fibrosis.

The finding that miR-21 is a major player in kidney fibrosis suggests that drugs that inhibit miR-21, like the complementary oligonucleotides used in this study, might prove to be useful therapies in humans.