Inhibiting MicroRNA-192 Ameliorates Renal Fibrosis in... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Inhibiting MicroRNA-192 Ameliorates Renal Fibrosis in Diabetic Nephropathy

Putta, Sumanth*,†; Lanting, Linda*; Sun, Guangdong*,‡; Lawson, Gregory§; Kato, Mitsuo*; Natarajan, Rama*,†

*Department of Diabetes and Division of Molecular Diabetes Research and

†Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California;

‡Department of Nephrology, Second Hospital of Jilin University, Changchun, Jilin, China; and

§Division of Laboratory Animal Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

Correspondence: Dr. Rama Natarajan or Dr. Mitsuo Kato, Department of Diabetes, Beckman Research Institute of the City of Hope. 1500 East Duarte Road, Duarte, CA 91010. Email: [email protected] or [email protected]

Received May 18, 2011

Accepted October 26, 2011

Abstract

TGF-_β_1 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.