title: Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1.
abstract: Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Gebeshuber
authors.forename: Christoph
authors.initials: C
authors.lastname: Kornauth
authors.forename: Lihua
authors.initials: L
authors.lastname: Dong
authors.forename: Ralph
authors.initials: R
authors.lastname: Sierig
authors.forename: Jost
authors.initials: J
authors.lastname: Seibler
authors.forename: Martina
authors.initials: M
authors.lastname: Reiss
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tauber
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Renate
authors.initials: R
authors.lastname: Kain
authors.forename: Georg A
authors.initials: GA
authors.lastname: Böhmig
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Christoph
authors.initials: C
authors.lastname: Englert
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D050199:Podocytes / Q000378:metabolism; D025721:WT1 Proteins / Q000502:physiology*
chemical_list: C546818:MIRN193 microRNA, human; C568257:MIRN193 microRNA, mouse; D035683:MicroRNAs; D025721:WT1 Proteins; D004318:Doxycycline