title: MicroRNA-193a Regulates the Transdifferentiation of Human Parietal Epithelial Cells toward a Podocyte Phenotype.
abstract: Parietal epithelial cells have been identified as potential progenitor cells in glomerular regeneration, but the molecular mechanisms underlying this process are not fully defined. Here, we established an immortalized polyclonal human parietal epithelial cell (hPEC) line from naive human Bowman's capsule cells isolated by mechanical microdissection. These hPECs expressed high levels of PEC-specific proteins and microRNA-193a (miR-193a), a suppressor of podocyte differentiation through downregulation of Wilms' tumor 1 in mice. We then investigated the function of miR-193a in the establishment of podocyte and PEC identity and determined whether inhibition of miR-193a influences the behavior of PECs in glomerular disease. After stable knockdown of miR-193a, hPECs adopted a podocyte-like morphology and marker expression, with decreased expression levels of PEC markers. In mice, inhibition of miR-193a by complementary locked nucleic acids resulted in an upregulation of the podocyte proteins synaptopodin and Wilms' tumor 1. Conversely, overexpression of miR-193a in vivo resulted in the upregulation of PEC markers and the loss of podocyte markers in isolated glomeruli. Inhibition of miR-193a in a mouse model of nephrotoxic nephritis resulted in reduced crescent formation and decreased proteinuria. Together, these results show the establishment of a human PEC line and suggest that miR-193a functions as a master switch, such that glomerular epithelial cells with high levels of miR-193a adopt a PEC phenotype and cells with low levels of miR-193a adopt a podocyte phenotype. miR-193a-mediated maintenance of PECs in an undifferentiated reactive state might be a prerequisite for PEC proliferation and migration in crescent formation.
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Leonie
authors.initials: L
authors.lastname: Kietzmann
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Sebastian S O
authors.initials: SS
authors.lastname: Guhr
authors.affiliation: Department of Internal Medicine, Nephrology, University Affiliated Asklepios Clinic Hamburg Barmbek, Hamburg, Germany;
authors.forename: Tobias N
authors.initials: TN
authors.lastname: Meyer
authors.affiliation: Childrens Renal Unit, Bristol Royal Hospital for Children, Bristol, United Kingdom; and.
authors.forename: Lan
authors.initials: L
authors.lastname: Ni
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Marlies
authors.initials: M
authors.lastname: Sachs
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.affiliation: Childrens Renal Unit, Bristol Royal Hospital for Children, Bristol, United Kingdom; and.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Gebeshuber
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; c.meyer-schwesinger@uke.uni-hamburg.de.
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
mesh_terms: D000818:Animals; D050476:Bowman Capsule / Q000166:cytology; D054338:Cell Transdifferentiation / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D018709:Statistics, Nonparametric
chemical_list: D035683:MicroRNAs
keywords: expression; podocyte; renal epithelial cell