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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Antibodies, Monoclonal
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Apoptosis
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Biomarkers / metabolism
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Line
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Cell Movement
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Cell Proliferation
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Claudin-1 / genetics
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Claudin-1 / metabolism
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Dibenzazepines / pharmacology
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Exotoxins
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Glomerulosclerosis, Focal Segmental / genetics
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Glomerulosclerosis, Focal Segmental / metabolism*
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Glomerulosclerosis, Focal Segmental / pathology
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Hyperplasia
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Integrases / genetics
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Integrases / metabolism
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Interleukin-2 Receptor alpha Subunit / genetics
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Interleukin-2 Receptor alpha Subunit / metabolism
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Jagged-1 Protein
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Kidney Glomerulus / drug effects
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Kidney Glomerulus / metabolism*
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Kidney Glomerulus / pathology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Podocytes / drug effects
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Podocytes / metabolism*
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Podocytes / pathology
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Proteinuria / genetics
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Proteinuria / metabolism
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Proteinuria / pathology
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RNA, Untranslated / genetics
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RNA, Untranslated / metabolism
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Receptor, Notch1 / antagonists & inhibitors
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Receptor, Notch1 / metabolism*
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Serrate-Jagged Proteins
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Time Factors
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Transcription Factor HES-1
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Transforming Growth Factor beta1 / metabolism
Substances
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Antibodies, Monoclonal
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B3(Fv)-PE38KDEL recombinant immunotoxin
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers
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Calcium-Binding Proteins
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Claudin-1
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Cldn1 protein, mouse
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Dibenzazepines
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Enzyme Inhibitors
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Exotoxins
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Gt(ROSA)26Sor non-coding RNA, mouse
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Hes1 protein, mouse
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Homeodomain Proteins
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IL2RA protein, human
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Intercellular Signaling Peptides and Proteins
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Interleukin-2 Receptor alpha Subunit
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Notch1 protein, mouse
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RNA, Untranslated
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Receptor, Notch1
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Serrate-Jagged Proteins
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TGFB1 protein, human
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Transcription Factor HES-1
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Transforming Growth Factor beta1
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nephrin
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Cre recombinase
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Integrases
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Amyloid Precursor Protein Secretases
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dibenzazepine