Tubule-Specific Mst1/2 Deficiency Induces CKD
Adaptor Proteins, Signal Transducing
/ physiology
Animals
Cell Cycle Proteins
/ physiology
Cells, Cultured
Fibrosis
Gene Expression Regulation
Hippo Signaling Pathway
In Situ Nick-End Labeling
Kidney
/ embryology
Kidney Tubules
/ enzymology
Male
Mice
Mice, Knockout
Mice, Transgenic
Phosphorylation
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases
/ deficiency
RNA Interference
RNA, Small Interfering
/ genetics
Renal Insufficiency, Chronic
/ enzymology
Serine-Threonine Kinase 3
Signal Transduction
Trans-Activators
/ physiology
Tumor Necrosis Factor-alpha
/ antagonists & inhibitors
YAP-Signaling Proteins
CKD
Hippo
MST1
MST2
YAP
renal fibrosis
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
14
10
2019
accepted:
14
02
2020
pubmed:
8
4
2020
medline:
29
12
2020
entrez:
8
4
2020
Statut:
ppublish
Résumé
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. We used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in 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- 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-
Sections du résumé
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
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-
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-
Identifiants
pubmed: 32253273
pii: ASN.2019101052
doi: 10.1681/ASN.2019101052
pmc: PMC7217407
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
RNA, Small Interfering
0
Trans-Activators
0
Tumor Necrosis Factor-alpha
0
Wwtr1 protein, mouse
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
Stk4 protein, mouse
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Serine-Threonine Kinase 3
EC 2.7.11.1
Stk3 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
946-961Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 by the American Society of Nephrology.
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