title: Effects of Shiga toxin type 2 on a bioengineered three-dimensional model of human renal tissue.
abstract: Shiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producing Escherichia coli (STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be more in vivo-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a more in vivo-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury.
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: DesRochers
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA.
authors.forename: Erica Palma
authors.initials: EP
authors.lastname: Kimmerling
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Dakshina M
authors.initials: DM
authors.lastname: Jandhyala
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: El-Jouni
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Cheleste M
authors.initials: CM
authors.lastname: Thorpe
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Leong
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA david.kaplan@tufts.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Kaplan
mesh_terms: D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000032:analysis; D008954:Models, Biological; D009924:Organ Culture Techniques; D009940:Organoids / Q000187:drug effects*; D011991:Receptors, Virus / Q000032:analysis; D022641:Shiga Toxin 2 / Q000633:toxicity*
chemical_list: C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D022641:Shiga Toxin 2