ROCK1 inhibitor stabilizes E-cadherin and improves barrier function in experimental necrotizing enterocolitis

Christie Buonpane, Carrie Yuan, Douglas Wood, Guillermo Ares, Samuel C. Klonoski, Catherine J. Hunter*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of newborns. Although incompletely understood, NEC is associated with intestinal barrier dysfunction. E-cadherin, an adherens junction, is a protein complex integral in maintaining normal barrier homeostasis. Rhoassociated protein kinase-1 (ROCK1) is a kinase that regulates the E-cadherin complex, and p120-catenin is a subunit of the E-cadherin complex that has been implicated in stabilizing the cadherin complex at the plasma membrane. We hypothesized that E-cadherin is decreased in NEC and that inhibition of ROCK1 would protect against adherens junction disruption. To investigate this, a multimodal approach was used: In vitro Caco-2 model of NEC (LPS/TNFα), rap pup model (hypoxia +bacteria-containing formula), and human intestinal samples. E-cadherin was decreased in NEC compared with controls, with relocalization from the cell border to an intracellular location. ROCK1 exhibited a time-dependent response to disease, with increased early expression in NEC and decreased expression at later time points and disease severity. Administration of ROCK1 inhibitor (RI) resulted in preservation of E-cadherin expression at the cell border, preservation of intestinal villi on histological examination, and decreased apoptosis. ROCK1 upregulation in NEC led to decreased association of E-cadherin to p120 and increased intestinal permeability. RI helped maintain the stability of the E-cadherin-p120 complex, leading to improved barrier integrity and protection from experimental NEC.

Original languageEnglish (US)
Pages (from-to)G781-G792
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume318
Issue number4
DOIs
StatePublished - 2020

Keywords

  • E-cadherin
  • Necrotizing enterocolitis
  • ROCK inhibitor

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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