title: MicroRNA-21 in glomerular injury.
abstract: TGF-β(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-β(1), and miR-21 inhibits apoptosis in cancer cells. TGF-β(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-β(1) and is higher in kidneys of TGF-β(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-β(1)-transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-β(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-β/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P<0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-β(1) and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21-deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF-β signaling and functions.
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Lai
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Pharmaceutical Sciences, Nanfang Hospital, Southern Medical University, Guangzhou, China;
authors.forename: Jinghui
authors.initials: J
authors.lastname: Luo
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Connor
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Jing
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ju
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Ann
authors.initials: A
authors.lastname: Randolph
authors.affiliation: Howard Hughes Medical Institute, The Rockefeller University, New York, New York;
authors.forename: Iddo Z
authors.initials: IZ
authors.lastname: Ben-Dov
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Regina N
authors.initials: RN
authors.lastname: Matar
authors.affiliation: Howard Hughes Medical Institute, The Rockefeller University, New York, New York;
authors.forename: Daniel
authors.initials: D
authors.lastname: Briskin
authors.affiliation: Department of Pathology and NYU Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York; and.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.affiliation: Howard Hughes Medical Institute, The Rockefeller University, New York, New York;
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York; markusbi@umich.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1
keywords: TGF-β; cell survival; diabetic glomerulopathy; molecular biology; podocyte