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bioRxiv · 10.1101/2021.04.15.440011

TAZ/TEAD complex regulates TGF-β1-mediated fibrosis in iPSC-derived renal organoids

Yang, X.·Delsante, M.·Deneshpajouhnejad, P.·Fenaroli, P.·Mandell, K. P.·Wang, X.·Takahashi, S.·Halushka, M. K.·Kopp, J. B.·Levi, M.·Rosenberg, A. Z.
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Abstract

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-{beta}1 induces production of extracellular matrix. In these organoids, TGF- {beta}1 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-11 (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-{beta}1-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.

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Yang, X., Delsante, M., Deneshpajouhnejad, P., Fenaroli, P., Mandell, K. P., Wang, X., Takahashi, S., Halushka, M. K., Kopp, J. B., Levi, M., Rosenberg, A. Z.. 2021-04-16. TAZ/TEAD complex regulates TGF-β1-mediated fibrosis in iPSC-derived renal organoids. https://doi.org/10.1101/2021.04.15.440011

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