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The consequences of increased 4E-BP1 in polycystic kidney disease.

Authors
  • Holditch, Sara J1
  • Brown, Carolyn N1
  • Atwood, Daniel J1
  • Pokhrel, Deepak1
  • Brown, Sara E1
  • Lombardi, Andrew M1
  • Nguyen, Khoa N1
  • Hill, Ryan C2
  • Lanaspa, Miguel1
  • Hopp, Katharina1
  • Weiser-Evans, Mary C M1
  • Edelstein, Charles L1
  • 1 Division of Renal Diseases and Hypertension, University of Colorado at Denver, Denver, CO, USA.
  • 2 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
Dec 15, 2019
Volume
28
Issue
24
Pages
4132–4147
Identifiers
DOI: 10.1093/hmg/ddz244
PMID: 31646342
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, characterized by cyst formation and growth. Hyperproliferation is a major contributor to cyst growth. At the nexus of regulating proliferation, is 4E-BP1. We demonstrate that ADPKD mouse and rat models, ADPKD patient renal biopsies and PKD1-/- cells exhibited hyperphosphorylated 4E-BP1, a biomarker of increased translation and proliferation. We hypothesized that expression of constitutively active 4E-BP1 constructs (4E-BP1F113A and 4E-BP1R13AF113A) would decrease proliferation and reduce cyst expansion. Utilizing the Pkd1RC/RC mouse, we determined the effect of 4E-BP1F113A on PKD. Unexpectedly, 4E-BP1F113A resulted in increased cyst burden and suppressed apoptosis markers, increased anti-apoptotic Bcl-2 protein and increased mitochondrial proteins. Exogenous 4E-BP1 enhanced proliferation, decreased apoptosis, increased anti-apoptotic Bcl-2 protein, impaired NADPH oxidoreductase activity, increased mitochondrial proteins and increased superoxide production in PKD patient-derived renal epithelial cells. Reduced 4E-BP1 expression suppressed proliferation, restored apoptosis and improved cellular metabolism. These findings provide insight into how cyst-lining cells respond to 4E-BP1. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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