Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype
Anorga, Sandybell; Overstreet, Jessica M; Falke, Lucas L; Tang, Jiaqi; Goldschmeding, Roel G; Higgins, Paul J; Samarakoon, Rohan
(2018) FASEB Journal, volume 32, issue 5, pp. 2644 - 2657
(Article)
Abstract
Although yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), nuclear transducers of the Hippo pathway, are mostly silent in adult organs, aberrant activation of YAP/TAZ promotes tumorigenesis and abnormal tissue repair. The extent of involvement of TAZ in chronic kidney disease (CKD) is unknown. In our study, increased
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TAZ nuclear accumulation and expression in the tubulointerstitium was readily evident in 3 models of renal injury including obstructive, aristolochic acid (AA), and diabetic nephropathy, correlating with fibrosis progression. Stable TAZ overexpression in human kidney (HK)-2 epithelial cells promoted connective tissue growth factor (CTGF), fibronectin, vimentin, and p21 expression, epithelial dedifferentiation, and growth inhibition, in part, via Sma mothers against decapentaplegic homologue (SMAD)-3-dependent CTGF induction. CTGF secretion by TAZ-overexpressing epithelium also triggered proliferative defects in nonengineered HK-2 cells confirming a nonautonomous role of TAZ (via a paracrine mechanism) in orchestrating kidney epithelial cell-cell communication. Renal tubular-specific induction of TGF-β1 in mice and TGF-β1 stimulation of HK-2 cells resulted in TAZ protein up-regulation. TAZ stable silencing in HK-2 cells abrogated TGF-β1-induced expression of target genes without affecting SMAD3 phosphorylation, which is also crucial for fibrotic reprogramming. Thus, TAZ was activated in fibrosis through TGF-β1-dependent mechanisms and sustained TAZ signaling promotes epithelial maladaptive repair. TAZ is also a novel non-SMAD downstream effector of renal TGF-β1 signaling, establishing TAZ as a new antifibrosis target for treatment of CKD.
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Keywords: Animals, Cell Line, Connective Tissue Growth Factor/genetics, Diabetic Nephropathies/genetics, Disease Models, Animal, Female, Fibrosis, Humans, Kidney Tubules, Proximal/metabolism, Male, Mice, Phosphorylation/genetics, Protein-Serine-Threonine Kinases/genetics, Renal Insufficiency, Chronic/genetics, Signal Transduction, Smad3 Protein/genetics, Transcription Factors/genetics, Transforming Growth Factor beta1/genetics, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN: 0892-6638
Publisher: FASEB
Note: Publisher Copyright: © 2018 FASEB.
(Peer reviewed)