Deregulation of Hippo–TAZ pathway during renal injury confers a fibrotic maladaptive phenotype

What is it about?

Effective treatments to halt chronic kidney disease (CKD) progression are currently lacking and, in this regard, uncovering novel mechanisms that mediate tubulointerstitial fibrosis is a significant step in developing future therapies. One of the recently identified dysregulated pathways involves the Hippo signaling network that regulates organ size. Involvement of the Hippo nuclear effector TAZ in CKD is unknown and is the subject of this investigation. Increased TAZ activation is readily evident in three models of renal injury including obstructive, aristolochic acid and diabetic nephropathy, correlating with fibrosis progression. Overexpression of the Hippo effector TAZ in human renal epithelial cells promotes fibrotic gene expression, epithelial dedifferentiation and growth inhibition. Secretion of the matrix protein CTGF induced by TAZ overexpression also triggered proliferative defects in the renal epithelium confirming the role of TAZ-induced soluble factors in orchestrating kidney epithelial cell-cell communication. TAZ stable silencing in kidney cells, furthermore, abrogated TGF-beta induced expression of target genes which is also crucial for fibrotic reprogramming. This work also identifies TGF-beta as an upstream regulator of TAZ activation. Thus, TAZ is activated in fibrosis through TGF-beta dependent mechanisms and sustained TAZ signaling promotes failed epithelial repair. TAZ is also a novel downstream effector of renal TGF-betasignaling, collectively establishing TAZ as a new "anti-fibrotic target" against CKD. Thus, targeting TAZ activation may be a novel and plausible strategy to halt CKD progression.

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