Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways

Immunopharmacol Immunotoxicol. 2024 Aug;46(4):509-520. doi: 10.1080/08923973.2024.2373216. Epub 2024 Jul 9.

Abstract

Background: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model.

Methods: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1β, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated.

Results: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen.

Conclusion: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.

Keywords: AMPK/Nrf2/HO-1; PPARγ/NF-κB; Vancomycin; acute renal injury; febuxostat; fenofibrate.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Acute Kidney Injury* / chemically induced
  • Acute Kidney Injury* / drug therapy
  • Acute Kidney Injury* / metabolism
  • Acute Kidney Injury* / pathology
  • Acute Kidney Injury* / prevention & control
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / toxicity
  • Cyclooxygenase 2 / metabolism
  • Febuxostat* / pharmacology
  • Heme Oxygenase (Decyclizing) / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • NF-E2-Related Factor 2* / metabolism
  • NF-kappa B* / metabolism
  • Oxidative Stress / drug effects
  • PPAR gamma
  • Rats
  • Rats, Wistar*
  • Signal Transduction* / drug effects
  • Vancomycin* / pharmacology
  • Vancomycin* / toxicity

Substances

  • AMP-Activated Protein Kinases
  • Anti-Bacterial Agents
  • Cyclooxygenase 2
  • Febuxostat
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, rat
  • PPAR gamma
  • PPAR gamma, rat
  • Ptgs2 protein, rat
  • Vancomycin