Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss

Toshiharu Ueno, Namiko Kobayashi, Makiko Nakayama, Yasutoshi Takashima, Takamoto Ohse, Ira Pastan, Jeffrey W. Pippin, Stuart J. Shankland, Noriko Uesugi, Taiji Matsusaka, Michio Nagata

    Research output: Contribution to journalArticlepeer-review

    45 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1065-1075
    Number of pages11
    JournalKidney international
    Volume83
    Issue number6
    DOIs
    Publication statusPublished - 2013 Jun

    Keywords

    • Focal segmental glomerulosclerosis
    • Notch signaling
    • Parietal epithelial cell
    • Podocyte loss

    ASJC Scopus subject areas

    • Nephrology

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