title: Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.
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.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.forename: Deidre A
authors.initials: DA
authors.lastname: MacKenna
authors.forename: Bryce G
authors.initials: BG
authors.lastname: Johnson
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaimal
authors.forename: Allie M
authors.initials: AM
authors.lastname: Roach
authors.forename: Shuyu
authors.initials: S
authors.lastname: Ren
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakagawa
authors.forename: Cuiyan
authors.initials: C
authors.lastname: Xin
authors.forename: Rick
authors.initials: R
authors.lastname: Newitt
authors.forename: Shweta
authors.initials: S
authors.lastname: Pandya
authors.forename: Tai-He
authors.initials: TH
authors.lastname: Xia
authors.forename: Xueqing
authors.initials: X
authors.lastname: Liu
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
authors.forename: Monica
authors.initials: M
authors.lastname: Grafals
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
authors.forename: Didier
authors.initials: D
authors.lastname: Portilla
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D024141:Collagen Type IV / Q000172:deficiency / Q000235:genetics; D018450:Disease Progression; D005355:Fibrosis / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D057507:Mice, 129 Strain; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009394:Nephritis, Hereditary / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020320:Oligoribonucleotides, Antisense / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D017382:Reactive Oxygen Species; C057112:type IV collagen alpha3 chain