Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy.
TGF-β1 upregulates microRNA-192 (miR-192) in cultured glomerular mesangial cells and in glomeruli from diabetic mice. miR-192 not only increases collagen expression by targeting the E-box repressors Zeb1/2 but also modulates other renal miRNAs, suggesting that it may be a therapeutic target for diabetic nephropathy. We evaluated the efficacy of a locked nucleic acid (LNA)-modified inhibitor of miR-192, designated LNA-anti-miR-192, in mouse models of diabetic nephropathy. LNA-anti-miR-192 significantly reduced levels of miR-192, but not miR-194, in kidneys of both normal and streptozotocin-induced diabetic mice. In the kidneys of diabetic mice, inhibition of miR-192 significantly increased Zeb1/2 and decreased gene expression of collagen, TGF-β, and fibronectin; immunostaining confirmed the downregulation of these mediators of renal fibrosis. Furthermore, LNA-anti-miR-192 attenuated proteinuria in these diabetic mice. In summary, the specific reduction of renal miR-192 decreases renal fibrosis and improves proteinuria, lending support for the possibility of an anti-miRNA-based translational approach to the treatment of diabetic nephropathy.
Department of Diabetes, Division of Molecular Diabetes Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Sumanth
S
Putta
Linda
L
Lanting
Guangdong
G
Sun
Gregory
G
Lawson
Mitsuo
M
Kato
Rama
R
Natarajan
D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D018398:Homeodomain Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D009841:Oligonucleotides / Q000494:pharmacology*; D011507:Proteinuria / Q000378:metabolism / Q000517:prevention & control; D012097:Repressor Proteins / Q000378:metabolism; D013311:Streptozocin / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
D005353:Fibronectins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse; D009841:Oligonucleotides; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C519422:ZEB1 protein, mouse; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C477371:locked nucleic acid; D013311:Streptozocin; D003094:Collagen