Aberrant Notch1-dependent Effects on Glomerular Parietal Epithelial Cells Promotes Collapsing Focal Segmental Glomerulosclerosis with Progressive Podocyte Loss

Overview

Journal Kidney Int

Publisher Elsevier

Specialty Nephrology

Date 2013 Mar 1

PMID 23447065

Citations 34

Authors

Toshiharu Ueno

Namiko Kobayashi

Makiko Nakayama

Yasutoshi Takashima

Takamoto Ohse

Ira Pastan

Jeffrey W Pippin

Stuart J Shankland

Noriko Uesugi

Taiji Matsusaka

Michio Nagata

Affiliations

Soon will be listed here.

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.

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