TY - JOUR
T1 - Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss
AU - Ueno, Toshiharu
AU - Kobayashi, Namiko
AU - Nakayama, Makiko
AU - Takashima, Yasutoshi
AU - Ohse, Takamoto
AU - Pastan, Ira
AU - Pippin, Jeffrey W.
AU - Shankland, Stuart J.
AU - Uesugi, Noriko
AU - Matsusaka, Taiji
AU - Nagata, Michio
N1 - Funding Information:
This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and was also supported by Grants-in-Aid for Scientific Research of Japan Society for the Promotion of Science (KAKEN; research project no. 22590877) and Progressive Renal Disease Research of the Ministry of Health, Labour and Welfare of Japan.
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - Focal segmental glomerulosclerosis
KW - Notch signaling
KW - Parietal epithelial cell
KW - Podocyte loss
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U2 - 10.1038/ki.2013.48
DO - 10.1038/ki.2013.48
M3 - Article
C2 - 23447065
AN - SCOPUS:84882248502
SN - 0085-2538
VL - 83
SP - 1065
EP - 1075
JO - Kidney International
JF - Kidney International
IS - 6
ER -