title: Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss.
abstract: Collapsing focal segmental glomerulosclerosis (cFSGS) is a progressive kidney disease characterized by glomerular collapse with epithelial hyperplasia. Here we used a transgenic mouse model of cFSGS with immunotoxin-induced podocyte-specific injury to determine the role for Notch signaling in its pathogenesis. The mice exhibited progressive loss of podocytes and severe proteinuria concomitant with histological features of cFSGS. Hyperplastic epithelium was negative for genetic podocyte tags, but positive for the parietal epithelial cell marker claudin-1, and expressed Notch1, Jagged1, and Hes1 mRNA and protein. Enhanced Notch mRNA expression induced by transforming growth factor-β1 in cultured parietal epithelial cells was associated with mesenchymal markers (α-smooth muscle actin, vimentin, and Snail1). Notch inhibition in vitro suppressed these phenotypic transcripts and Notch-dependent cell migration. Moreover, Notch inhibition in vivo significantly decreased parietal epithelial cell lesions but worsened proteinuria and histopathology in our cFSGS model. Thus, aberrant Notch1-mediated parietal epithelial cell migration with phenotypic changes appears to underlie the pathogenesis of cFSGS. Parietal epithelial cell hyperplasia may also represent an adaptive response to compensate for a disrupted filtration barrier with progressive podocyte loss.
authors: Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors: Toshiharu
authors: T
authors: Ueno
authors: Namiko
authors: N
authors: Kobayashi
authors: Makiko
authors: M
authors: Nakayama
authors: Yasutoshi
authors: Y
authors: Takashima
authors: Takamoto
authors: T
authors: Ohse
authors: Ira
authors: I
authors: Pastan
authors: Jeffrey W
authors: JW
authors: Pippin
authors: Stuart J
authors: SJ
authors: Shankland
authors: Noriko
authors: N
authors: Uesugi
authors: Taiji
authors: T
authors: Matsusaka
authors: Michio
authors: M
authors: Nagata
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005098:Exotoxins; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D013997:Time Factors; D000072056:Transcription Factor HES-1; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000911:Antibodies, Monoclonal; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D062445:Claudin-1; D003984:Dibenzazepines; D004791:Enzyme Inhibitors; D005098:Exotoxins; D018398:Homeodomain Proteins; D019426:Integrases; D036341:Intercellular Signaling Peptides and Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D022661:RNA, Untranslated; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; D053773:Transforming Growth Factor beta1; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; C568113:Cldn1 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C489734:Hes1 protein, mouse; C508017:IL2RA protein, human; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497762:Notch1 protein, mouse; C508960:TGFB1 protein, human; C113267:nephrin; C045073:Cre recombinase; C527817:dibenzazepine