HIF stabilization inhibits renal epithelial cell migration and is associated with cytoskeletal alterations

Sci Rep. 2018 Jun 22;8(1):9497. doi: 10.1038/s41598-018-27918-9.

Abstract

Acute kidney injury (AKI) is a common and potentially lethal complication in the hospitalized patients, with hypoxic injury being as a major cause. The loss of renal tubular epithelial cells (TEC), one of the AKI hallmarks, is potentially followed by tubular regeneration process orchestrated by the remaining uninjured TECs that undergo proliferation and migration. In this study, we used human primary TEC to investigate the initiation of tubular cell migration and associated cytoskeletal alterations in response to pharmacological HIF stabilization which resembles the pathophysiology of hypoxia. Tubular cells have been shown to migrate as cohorts in a wound healing assay. Importantly, cells of distal tubular origin moved faster than those of proximal origin. HIF stabilization impaired TEC migration, which was confirmed by live single cell tracking. HIF stabilization significantly reduced tubular cell migration velocity and promoted cell spreading. In contrast to the control conditions, HIF stabilization induced actin filaments rearrangement and cell adhesion molecules including paxillin and focal adhesion kinase. Condensed bundling of keratin fibers was also observed, while the expression of different types of keratins, phosphorylation of keratin 18, and the microtubule structure were not altered. In summary, HIF stabilization reduced the ability of renal tubular cells to migrate and led to cytoskeleton reorganization. Our data suggested an important involvement of HIF stabilization during the epithelial migration underlying the mechanism of renal regeneration in response to AKI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Adhesion / drug effects
  • Cell Line
  • Cell Movement* / drug effects
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism*
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Keratins / metabolism
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Phosphorylation / drug effects
  • Protein Stability

Substances

  • Amino Acids, Dicarboxylic
  • Basic Helix-Loop-Helix Transcription Factors
  • Keratins
  • oxalylglycine