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首页> 外文期刊>Journal of Pathology: Journal of the Pathological Society of Great Britain and Ireland >Kidney-specific knockout of Sav1 in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway
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Kidney-specific knockout of Sav1 in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

机译：小鼠Sav1的肾脏特异性敲除通过抑制Hippo途径促进肾小管上皮过度增殖

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摘要

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. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
机译：先前我们曾报道过，由于14q拷贝数减少，在高级透明细胞肾细胞癌（ccRCC）中，萨尔瓦多同源物1（SAV1）是Hippo通路的一个成分，其表达明显下调，并且这种下调有助于通过激活Yes相关蛋白1（YAP1）（河马通路的下游靶标）激活肾小管上皮细胞的增殖和存活。但是，SAV1丢失对体内肾细胞增殖和存活的影响尚待确定。为了解决此问题，我们生成了肾脏特异性Sav1-knockout（Cdh16-Cre; Sav1（fl / fl））小鼠。 Sav1缺乏会增强Cdh16-Cre; Sav1（fl / fl）小鼠肾小管上皮细胞的增殖，并伴随Yap1的核定位，表明抑制了Hippo途径。肾小管的Sav1缺乏也会引起上皮细胞的结构和细胞异常，包括其核的显着增大。此外，Cdh16-Cre; Sav1（fl / fl）小鼠发展了肾小球和肾小管囊肿。尽管肾小球囊肿的衬里细胞没有显示异型性，但肾小管囊肿的衬里细胞却显示出细胞大小和核形状的变化，随着小鼠的衰老，这种情况变得更加严重。在老年Cdh16-Cre; Sav1（fl / fl）小鼠中，我们观察到近端小管的局灶性破坏和血管周淋巴细胞浸润。总之，Sav1是在生理条件下维持肾小管的生长，核大小和结构所必需的，其缺乏导致通过抑制Hippo信号传导获得增强的肾上皮细胞增殖。版权所有（c）2016英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版

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