Omeprazole induces profibrotic gene expression in rat kidney: implication of TGF-β/Smad signaling pathway

Drug Chem Toxicol. 2024 Sep;47(5):748-755. doi: 10.1080/01480545.2023.2282377. Epub 2023 Nov 20.

Abstract

Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications. However, PPI usage is linked to a higher risk of both acute and chronic renal damage by mechanisms not entirely known. The present study demonstrates that omeprazole (10 mg/kg body weight, i.p.) causes TGF-β/Smad signaling activation and subsequent expression of the profibrotic genes CTGF and TIMP-1 in rat kidney. Increased production of CTGF and TIMP-1 accompany activation of the TGF-β/Smad signaling cascade. However, simultaneous treatment of omeprazole and the TGF-β inhibitor, disitertide (P144) (1 mg/kg body weight i.p.) suppresses the TGF-β/Smad signaling pathway and subsequent production of CTGF and TIMP-1. Additionally, TGF-β level in rat kidney was highly reduced in animals treated with the ROS (reactive oxygen species) scavenger, N-acetyl cysteine (NAC) (100 mg/kg body weight i.p.) before omeprazole administration. Furthermore, the reduction in SOD activity brought by omeprazole was returned to the normal level in those animals. However, MDA level increased by omeprazole was highly reduced in the presence of NAC. Collectively, the current findings demonstrate that omeprazole has the ability to promote the expression of the profibrotic genes CTGF and TIMP-1 in a ROS and TGF-β dependent manner. The present study suggests the co-use of ROS scavenger to improve the therapeutic use of the PPI omeprazole.

Keywords: Omeprazole; ROS; TGF-β/Smad signaling; fibrosis; kidney.

MeSH terms

  • Animals
  • Connective Tissue Growth Factor* / genetics
  • Connective Tissue Growth Factor* / metabolism
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Kidney* / drug effects
  • Kidney* / metabolism
  • Male
  • Omeprazole* / pharmacology
  • Proton Pump Inhibitors* / pharmacology
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Signal Transduction* / drug effects
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-1* / genetics
  • Tissue Inhibitor of Metalloproteinase-1* / metabolism
  • Transforming Growth Factor beta* / genetics
  • Transforming Growth Factor beta* / metabolism

Substances

  • Omeprazole
  • Proton Pump Inhibitors
  • CCN2 protein, rat
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor
  • Tissue Inhibitor of Metalloproteinase-1
  • TIMP1 protein, rat
  • Reactive Oxygen Species
  • Smad Proteins