title: 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.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Kölling
authors.affiliation: Institute of Pathophysiology, Semmelweis University, 1085 Budapest, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kaucsar
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Celina
authors.initials: C
authors.lastname: Schauerte
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Hübner
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Dettling
authors.affiliation: Department of Nephrology, Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Internal Medicine III/Nephrology, Jena University Hospital, 07747 Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Busch
authors.affiliation: Department of Internal Medicine III/Nephrology, Jena University Hospital, 07747 Jena, Germany.
authors.forename: Xaver
authors.initials: X
authors.lastname: Wulff
authors.affiliation: Department of Nephrology, Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Meier
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Scherf
authors.affiliation: Institute of Pathophysiology, Semmelweis University, 1085 Budapest, Hungary.
authors.forename: Nóra
authors.initials: N
authors.lastname: Bukosza
authors.affiliation: Institute of Pathophysiology, Semmelweis University, 1085 Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
authors.affiliation: Institute of Pathophysiology, Semmelweis University, 1085 Budapest, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Godó
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Institute of Pathophysiology, Semmelweis University, 1085 Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Hamar
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bang
authors.affiliation: Department of Nephrology, Hanover Medical School, 30625 Hannover, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany; National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK. Electronic address: thum.thomas@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hanover Medical School, 30625 Hannover, Germany; Department of Nephrology, Hanover Medical School, 30625 Hannover, Germany; Division of Nephrology, University Hospital Zürich, 8091 Zürich, Switzerland. Electronic address: johan.lorenzen@usz.ch.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Lorenzen
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002465:Cell Movement; D016000:Cluster Analysis; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D050199:Podocytes / Q000378:metabolism; D034622:RNA Interference; D020687:cdc25 Phosphatases / Q000235:genetics
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051361:Cyclin-Dependent Kinase 6; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases
keywords: TGF-β; cell-cycle regulators; diabetic nephropathy; mesangial hypertrophy; miR-21; microRNA; podocyte motility