[HTML][HTML] Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

IG Gomez, DA MacKenna, BG Johnson… - The Journal of …, 2015 - Am Soc Clin Investig
IG Gomez, DA MacKenna, BG Johnson, V Kaimal, AM Roach, S Ren, N Nakagawa, C Xin…
The Journal of clinical investigation, 2015Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation