Tubule-Specific Mst1/2 Deficiency Induces CKD via YAP and Non-YAP Mechanisms

摘要

abstract_textpSignificance StatementThe serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, and Yes-associated protein (YAP) is one of the pathway?s main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the role of MST1 and MST2 in the kidney has not been studied. In studies using knockout mice (with tubule-specific deletion of both Mst1 and Mst2) and mouse inner medullary collecting duct cells, the authors demonstrate that tubular deletion of Mst1 and Mst2 activates YAP, which induces inflammation, tubular lesions, fibrosis, and functional impairment; they also show that pathogenesis involves reciprocal stimulation of TNF-? and YAP signaling activities. Their findings indicate that tubular YAP activation induces renal fibrosis and CKD, thus revealing a novel and critical mechanism underlying this condition. BackgroundThe serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, which has been found to be critically involved in embryonic kidney development. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the pathway?s main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the functional role of MST1 and MST2 in the kidney has not been studied.MethodsWe used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in Drosophila. We generated mice with tubule-specific double knockout of Mst1 and Mst2 or triple knockout of Mst1, Mst2, and Yap. PCR array and mouse inner medullary collecting duct cells were used to identify the primary target of Mst1/Mst2 deficiency.ResultsMST1 and MST2 were predominantly expressed in the tubular epithelial cells of adult kidneys. Deletion of Mst1/Mst2 in renal tubules increased activity of YAP but not TAZ. The kidneys of mutant mice showed progressive inflammation, tubular and glomerular damage, fibrosis, and functional impairment; these phenotypes were largely rescued by deletion of Yap in renal tubules. TNF-? expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-? and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2.ConclusionsOur findings show that tubular Mst1/Mst2 deficiency leads to CKD through both the YAP and non-YAP pathways and that tubular YAP activation induces renal fibrosis. The pathogenesis seems to involve the reciprocal stimulation of TNF-? and YAP signaling activities./p/abstract_text