Kidney-specific knockout of Sav1 in the mouse promotes hyper-proliferation of renal tubular epithelium through suppression of the Hippo pathway

Abstract

Previously, we have reported that Salvador homolog 1 (SAV1), a component of the Hippo pathway, is significantly downregulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this downregulation 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 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 maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.

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