Therapeutic miR-21 Silencing Ameliorates Diabetic Kidney Disease in Mice.

Abstract

Diabetic nephropathy is the main cause of end-stage renal disease. MicroRNAs are powerful regulators of the genome, and global expression profiling revealed miR-21 to be among the most highly regulated microRNAs in kidneys of mice with diabetic nephropathy. In kidney biopsies of diabetic patients, miR-21 correlated with tubulointerstitial injury. In situ PCR analysis showed a specific enrichment of miR-21 in glomerular cells. We identified cell division cycle 25a (Cdc25a) and cyclin-dependent kinase 6 (Cdk6) as novel miR-21 targets in mesangial cells. miR-21-mediated repression of Cdc25a and Cdk6 resulted in impaired cell cycle progression and subsequent mesangial cell hypertrophy. miR-21 increased podocyte motility by regulating phosphatase and tensin homolog (Pten). miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression. In conclusion, miR-21 antagonism rescued various functional and structural parameters in mice with diabetic nephropathy and, thus, might be a viable option in the treatment of patients with diabetic kidney disease.

• Authors: Malte Kölling, Tamas Kaucsar, Celina Schauerte, Anika Hübner, Angela Dettling, Joon-Keun Park, Martin Busch, Xaver Wulff, Matthias Meier, Kristian Scherf, Nóra Bukosza, Gábor Szénási, Mária Godó, Amit Sharma, Michael Heuser, Peter Hamar, Claudia Bang, Hermann Haller, Thomas Thum, Johan M Lorenzen
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 25 Issue 1 Pg. 165-180 (01 04 2017) ISSN: 1525-0024 [Electronic] United States
• PMID: 28129112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• MIRN21 microRNA, mouse
• MicroRNAs
• Cyclin-Dependent Kinase 6
• Cdc25a protein, mouse
• cdc25 Phosphatases

Topics

• Animals
• Cell Cycle Checkpoints (genetics)
• Cell Movement
• Cluster Analysis
• Cyclin-Dependent Kinase 6 (genetics)
• Diabetes Mellitus, Experimental
• Diabetic Nephropathies (genetics, metabolism, pathology, therapy)
• Disease Models, Animal
• Fibrosis
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Silencing
• Inflammation (genetics, metabolism, pathology)
• Kidney Glomerulus (metabolism, pathology)
• Mesangial Cells (metabolism)
• Mice
• MicroRNAs (genetics)
• Podocytes (metabolism)
• RNA Interference
• cdc25 Phosphatases (genetics)