Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice

Zheng Wang, Alex Divanyan, Frances L. Jourd’heuil, Robert D. Goldman, Karen M. Ridge, David Jourd’heuil, Reynold I. Lopez-Soler*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Vimentin expression is re-quired for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice. Am J Physiol Renal Physiol 315: F769–F780, 2018. First published April 4, 2018; doi:10.1152/ajprenal.00340.2017.—Most renal transplants ultimately fail secondary to chronic allograft nephropathy (CAN). Vimentin (vim) is a member of the intermediate filament family of proteins and has been shown to be important in the development of CAN. One of the pathways leading to chronic renal fibrosis after transplant is thought to be epithelial to mesenchymal transition (EMT). Even though vim expression is one of the main steps of EMT, it is unknown whether vim expression is required for EMT leading to renal fibrosis and allograft loss. To this end, the role of vim in renal fibrosis was determined via unilateral ureteral obstruction (UUO) in vim knockout mice (129 svs6 vim −/−). Following UUO, kidneys were recovered and analyzed via Western blotting, immunofluorescence, and tran-scriptomics. Cultured human proximal renal tubular (HK-2) cells were subjected to lentiviral-driven inhibition of vim expression and then treated with transforming growth factor (TGF)-β to undergo EMT. Immunoblotting as well as wound healing assays were used to determine development of EMT. Western blotting analyses of mice undergoing UUO reveal increased levels of vim soon after UUO. As expected, interstitial collagen deposition increased in control mice following UUO but decreased in vim −/− kidneys. Immunofluorescence analyses also revealed altered localization of β-catenin in vim −/− mice undergoing UUO without significant changes in mRNA levels. However, RNA sequencing revealed a decrease in β-catenin-dependent genes in vim −/− kidneys. Finally, vim-silenced HK-2 cell lines undergoing EMT were shown to have decreased cellular migration during wound healing. We conclude that vim inhibition decreases fibrosis following UUO by possibly altering β-catenin localization and downstream signaling.

Original languageEnglish (US)
Pages (from-to)F769-F780
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number4
DOIs
StatePublished - Oct 2018

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Keywords

  • Can
  • Emt
  • Fibrosis
  • Renal transplant
  • Vimentin
  • β-catenin

ASJC Scopus subject areas

  • Physiology
  • Urology

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