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Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. | LitMetric

AI Article Synopsis

  • * Researchers created specific oligonucleotides that target and inhibit miR-21 in the kidneys, which showed promising results in a mouse model of Alport nephropathy, leading to milder disease symptoms and improved survival rates.
  • * Silencing miR-21 not only preserved kidney function by enhancing mitochondrial performance and reducing inflammation but also suggested a potential therapeutic approach for chronic kidney diseases.

Article Abstract

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 PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382246PMC
http://dx.doi.org/10.1172/JCI75852DOI Listing

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