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Adriamycin-Induced Podocyte Injury Disrupts the YAP-TEAD1 Axis and Downregulates Cyr61 and CTGF Expression

  • Morgan A. Burt
    Morgan A. Burt
    Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
  • Titilola D. Kalejaiye
    Titilola D. Kalejaiye
    Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
  • Rohan Bhattacharya
    Rohan Bhattacharya
    Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
    Center for Biomolecular and Tissue Engineering, Duke University, Durham, North Carolina 27708, United States
  • Nikolaos Dimitrakakis
    Nikolaos Dimitrakakis
    Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States
  • , and 
  • Samira Musah*
    Samira Musah
    Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
    Center for Biomolecular and Tissue Engineering, Duke University, Durham, North Carolina 27708, United States
    Department of Medicine, Division of Nephrology, Duke University School of Medicine, Durham, North Carolina 27710, United States
    Department of Cell Biology, Duke University, Durham, North Carolina 27710, United States
    *E-mail: [email protected]
    More by Samira Musah
Cite this: ACS Chem. Biol. 2022, 17, 12, 3341–3351
Publication Date (Web):December 10, 2021
https://doi.org/10.1021/acschembio.1c00678
Copyright © 2021 American Chemical Society

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    Abstract

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    The most severe forms of kidney diseases are often associated with irreversible damage to the glomerular podocytes, the highly specialized epithelial cells that encase glomerular capillaries and regulate the removal of toxins and waste from the blood. Several studies revealed significant changes to podocyte cytoskeletal structure during disease onset, suggesting possible roles of cellular mechanosensing in podocyte responses to injury. Still, this topic remains underexplored partly due to the lack of appropriate in vitro models that closely recapitulate human podocyte biology. Here, we leveraged our previously established method for the derivation of mature podocytes from human induced pluripotent stem cells (hiPSCs) to help uncover the roles of yes-associated protein (YAP), a transcriptional coactivator and mechanosensor, in podocyte injury response. We found that while the total expression levels of YAP remain relatively unchanged during Adriamycin (ADR)-induced podocyte injury, the YAP target genes connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (Cyr61) are significantly downregulated. Intriguingly, TEAD1 is significantly downregulated in podocytes injured with ADR. By examining multiple independent modes of cellular injury, we found that CTGF and Cyr61 expression are downregulated only when podocytes were exposed to molecules known to disrupt the cell’s mechanical integrity or cytoskeletal structure. To our knowledge, this is the first report that the YAP-TEAD1 signaling axis is disrupted when stem cell-derived human podocytes experience biomechanical injury. Together, these results could help improve the understanding of kidney disease mechanisms and highlight CTGF and Cyr61 as potential therapeutic targets or biomarkers for patient stratification.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.1c00678.

    • Additional phase contrast images of injured hiPSC-podocytes, microarray analysis of TEAD and YAP target gene expression in hiPSCs and hiPSC-podocytes, and the sequences of all qPCR primers used in this study (PDF)

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    Cited By

    This article is cited by 2 publications.

    1. Alex Eve. Transitions in development – an interview with Samira Musah. Development 2023, 150 (2) https://doi.org/10.1242/dev.201539
    2. Jennifer Cable, Matthias P. Lutolf, Jianping Fu, Sunghee Estelle Park, Athanasia Apostolou, Shuibing Chen, Cheng Jack Song, Jason R. Spence, Prisca Liberali, Madeline Lancaster, Anna B. Meier, Nicole Min Qian Pek, James M. Wells, Meghan M. Capeling, Ana Uzquiano, Samira Musah, Meritxell Huch, Mina Gouti, Pleun Hombrink, Giorgia Quadrato, Jean‐Paul Urenda. Organoids as tools for fundamental discovery and translation—a Keystone Symposia report. Annals of the New York Academy of Sciences 2022, 1518 (1) , 196-208. https://doi.org/10.1111/nyas.14874

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