TY - JOUR T1 - TAZ/TEAD complex regulates TGF-β1-mediated fibrosis in iPSC-derived renal organoids JF - bioRxiv DO - 10.1101/2021.04.15.440011 SP - 2021.04.15.440011 AU - Xiaoping Yang AU - Marco Delsante AU - Parnaz Daneshpajouhnejad AU - Paride Fenaroli AU - Kira Perzel Mandell AU - Xiaoxin Wang AU - Shogo Takahashi AU - Marc K. Halushka AU - Jeffrey B. Kopp AU - Moshe Levi AU - Avi Z. Rosenberg Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/04/15/2021.04.15.440011.abstract N2 - Chronic kidney disease (CKD) progresses by replacement of functional tissue compartments with fibrosis, representing a maladaptive repair process. Shifting kidney repair towards a physiologically-intact architecture, rather than fibrosis, is key to blocking CKD progression. In this study, we developed a fibrosis model that uses human induced pluripotent stem cell (iPSC)-based three-dimensional renal organoids, in which exogenous TGF-β1 induces production of extracellular matrix. In these organoids, TGF- β1 increased transcription factor tafazzin (TAZ) expression. Further, in human kidney biopsies, nuclear TAZ expression was markedly increased in mild and moderate fibrosis. In cultured renal tubular cells expressing a fibrogenic program, TAZ formed a trimeric complex with phosphorylated mothers against decapentaplegic homolog 3 (p-SMAD3) and TEA domain protein (TEAD)-4. Overexpression of TEAD4 protein suppressed collagen-1α1 (COL1A1) promoter activity, and expression of TAZ attenuated this inhibition. INT-767, a dual bile acid receptor agonist binding farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5), decreased the TGF-β1-induced increase in p-SMAD3 and TAZ, and preserved renal organoid architecture. These data demonstrate, in an iPSC-derived renal organoid fibrosis model, that INT767 prevents fibrosis programs early in the course of tubular injury through modulation of the TEAD4/TAZ pathway.Competing Interest StatementThe authors have declared no competing interest. ER -