Activation of transient receptor potential vanilloid channel 4 contributes to the development of ethanol-induced gastric injury in mice

Eur J Pharmacol. 2021 Jul 5;902:174113. doi: 10.1016/j.ejphar.2021.174113. Epub 2021 Apr 24.

Abstract

The transient receptor potential vanilloid channel 4 (TRPV4) is associated with the development of several pathologies, particularly gastric disorders. However, there are no studies associating this receptor with the pathophysiology of gastric erosions. The aim of this study was to investigate the role of TRPV4 in the development of ethanol-induced gastric damage in vivo. Gastric lesions were induced by ethanol in Swiss mice pretreated with TRPV4 antagonists, GSK2193874 (0.1; 0.3 and 0.9 mg/kg) or Ruthenium red (0.03; 0.1 or 0.3 mg/kg) or its agonist, GSK1016790A (0.9 mg/kg). Gastric mucosal samples were taken for histopathology, immunohistochemistry, atomic force microscopy and evaluation of antioxidant parameters. The gastric mucus content and TRPV4 mRNA expression were analyzed. Ethanol exposure induced upregulation of gastric mRNA and protein expression of TRPV4. TRPV4 blockade promoted gastroprotection against ethanol-induced injury on macro- and microscopic levels, leading to reduced hemorrhage, cell loss and edema and enhanced gastric mucosal integrity. Moreover, an increase in superoxide dismutase (SOD) and glutathione (GSH) activity was observed, followed by a decrease in malondialdehyde (MDA) levels. TRPV4 blockade during alcohol challenge reestablished gastric mucus content. The combination of TRPV4 agonist and ethanol revealed macroscopic exacerbation of gastric damage area. Our results confirmed the association of TRPV4 with the development of gastric injury, showing the importance of this receptor for further investigations in the field of gastrointestinal pathophysiology and pharmacology.

Keywords: Vanilloid receptors. gastric damage. Mucosal inflammation. TRPV4.

MeSH terms

  • Animals
  • Edema / chemically induced
  • Edema / metabolism
  • Ethanol / toxicity
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / injuries
  • Gastric Mucosa / metabolism
  • Glutathione / metabolism
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Leucine / therapeutic use
  • Male
  • Malondialdehyde / metabolism
  • Mice
  • Oxidative Stress / drug effects
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Quinolines / pharmacology
  • Quinolines / therapeutic use
  • Ruthenium Red / pharmacology
  • Ruthenium Red / therapeutic use
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / metabolism*
  • Stomach Ulcer / pathology
  • Stomach Ulcer / physiopathology*
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Superoxide Dismutase / metabolism
  • TRPV Cation Channels / agonists*
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Up-Regulation / drug effects

Substances

  • GSK2193874
  • N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
  • Piperidines
  • Quinolines
  • Sulfonamides
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Ruthenium Red
  • Ethanol
  • Malondialdehyde
  • Superoxide Dismutase
  • Glutathione
  • Leucine