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Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

Authors :
Masahito Ikawa
Takeo Nomura
Tsutomu Daa
Hidekatsu Iha
Chisato Nakada
Keiko Matsuura
Mika Takahashi
Masatsugu Moriyama
Akinori Tokunaga
Masao Seto
Yoshiyuki Tsukamoto
Naoki Hijiya
Hiromitsu Mimata
Tomohisa Uchida
Fuminori Sato
Tomoki Kai
Source :
The Journal of Pathology. 239:97-108
Publication Year :
2016
Publisher :
Wiley, 2016.

Abstract

We have previously reported that Salvador homologue 1 (SAV1), a component of the Hippo pathway, is significantly down-regulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this down-regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes-associated protein 1 (YAP1), a downstream target of the Hippo pathway. However, the impact of SAV1 loss on the proliferation and survival of kidney cells in vivo remained to be determined. To address this issue, we generated kidney-specific Sav1-knockout (Cdh16-Cre;Sav1(fl/fl) ) mice. Sav1 deficiency enhanced the proliferation of renal tubular epithelial cells in Cdh16-Cre;Sav1(fl/fl) mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. Sav1 deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, Cdh16-Cre;Sav1(fl/fl) mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged Cdh16-Cre;Sav1(fl/fl) mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, Sav1 is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.

Details

ISSN :
00223417
Volume :
239
Database :
OpenAIRE
Journal :
The Journal of Pathology
Accession number :
edsair.doi...........e6317e30a295a43422ef06958e313287
Full Text :
https://doi.org/10.1002/path.4706