Chunhua Xu1, Li Wang1, Yu Zhang1, Wenling Li1, Jinhong Li2, Yang Wang1, Chenling Meng1, Jinzhong Qin3, Zhi-Hua Zheng2, Hui-Yao Lan4, Kingston King-Lun Mak5, Yu Huang1, Yin Xia6,7. 1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 2. Department of Nephrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China. 3. The Key Laboratory of Model Animal for Disease Study, Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China. 4. Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. 5. Guangzhou Regenerative Medicine and Health-Guangdong Laboratory, Guangzhou, China. 6. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China Xia.Yin@cuhk.edu.hk. 7. Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Abstract
BACKGROUND: The 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. METHODS: We 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. RESULTS: MST1 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-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2. CONCLUSIONS: Our 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-α and YAP signaling activities.
BACKGROUND: The 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. METHODS: We 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. RESULTS:MST1 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-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2. CONCLUSIONS: Our 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-α and YAP signaling activities.
Authors: Thijs J Hagenbeek; Joshua D Webster; Noelyn M Kljavin; Matthew T Chang; Trang Pham; Ho-June Lee; Christiaan Klijn; Allen G Cai; Klara Totpal; Buvana Ravishankar; Naiying Yang; Da-Hye Lee; Kevin B Walsh; Georgia Hatzivassiliou; Cecile C de la Cruz; Stephen E Gould; Xiumin Wu; Wyne P Lee; Shuqun Yang; Zhixiang Zhang; Qingyang Gu; Qunsheng Ji; Erica L Jackson; Dae-Sik Lim; Anwesha Dey Journal: Sci Signal Date: 2018-09-11 Impact factor: 8.192
Authors: Antoine Reginensi; Leonie Enderle; Alex Gregorieff; Randy L Johnson; Jeffrey L Wrana; Helen McNeill Journal: Nat Commun Date: 2016-08-02 Impact factor: 14.919
Authors: Rebeca González-Fernández; María Ángeles González-Nicolás; Manuel Morales; Julio Ávila; Alberto Lázaro; Pablo Martín-Vasallo Journal: Cells Date: 2022-05-09 Impact factor: 7.666