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Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways
Ivan G. Gomez, … , B. Nelson Chau, Jeremy S. Duffield
Ivan G. Gomez, … , B. Nelson Chau, Jeremy S. Duffield
Published November 21, 2014
Citation Information: J Clin Invest. 2015;125(1):141-156. https://doi.org/10.1172/JCI75852.
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Research Article Nephrology

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

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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.

Authors

Ivan G. Gomez, Deidre A. MacKenna, Bryce G. Johnson, Vivek Kaimal, Allie M. Roach, Shuyu Ren, Naoki Nakagawa, Cuiyan Xin, Rick Newitt, Shweta Pandya, Tai-He Xia, Xueqing Liu, Dorin-Bogdan Borza, Monica Grafals, Stuart J. Shankland, Jonathan Himmelfarb, Didier Portilla, Shiguang Liu, B. Nelson Chau, Jeremy S. Duffield

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Figure 1

miR-21 upregulation in Alport nephropathy precedes histological changes in the kidney.

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miR-21 upregulation in Alport nephropathy precedes histological changes ...
(A) Schema showing the sequence and configuration of human (hsa) pre–miR-21, the processed mature miR-21. The domain that binds to 3′ UTR regions of translated mRNA by sequence complementarity is highlighted. (B) Quantitative reverse-transcriptase PCR (qRT-PCR) for miR-21 copy number in tubules and glomeruli of Col4a3–/– kidneys purified by laser-capture microdissection. (C) qPCR levels for miR-21 in whole kidney from Col4a3–/– mice compared with heterozygotes. (D) PAS-stained images of kidney cortex from Col4a3–/– mice or heterozygotes showing essentially normal histology at 3 weeks and rare segmental sclerosis of glomeruli (arrow) at 5 weeks. The tubules appear normal. Scale bars: 50 μm. n = 3–6/group. *P < 0.05, 1-way ANOVA or Mann-Whitney U test)
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