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Polymyxin B exerts nephrotoxicity effects via inhibition of the Nrf2/NQO1 pathway-mediated antioxidant response

Guiying Xiao1,2,3, Fang Yuan1,2, Yang Deng1,2

  • 1Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan, China.

Journal of Biochemical and Molecular Toxicology
|March 30, 2023
PubMed

Insights

Polymyxin B causes kidney damage by inhibiting the Nrf2/NQO1 pathway, leading to oxidative stress and apoptosis. This study clarifies the molecular mechanisms behind this nephrotoxicity.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Toxicology

Background:

  • Polymyxin B (PMB) is crucial for treating multidrug-resistant Gram-negative bacterial infections.
  • Nephrotoxicity is a significant limitation to clinical Polymyxin B use.
  • Understanding the molecular mechanisms of PMB-induced kidney injury is essential.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying Polymyxin B-induced nephrotoxicity.
  • To explore the role of oxidative stress and apoptosis in PMB-induced renal injury.
  • To examine the involvement of the Nrf2/NQO1 pathway in Polymyxin B nephrotoxicity.

Main Methods:

  • Constructed a kidney injury model in mice and utilized NRK-52E cells for in vitro studies.
  • Assessed antioxidant capacity by measuring SOD, CAT, GSH, and MDA levels.
  • Evaluated the Nrf2/NQO1 pathway and apoptosis-related gene/protein expression (Bax, Bcl-2, Caspase-3, Caspase-9) using qPCR and Western blot.

Main Results:

  • Polymyxin B induced nephrotoxicity in a dose- and time-dependent manner in vivo and in vitro.
  • PMB treatment reduced the expression of Nrf2 and its downstream target NQO1.
  • PMB increased the expression of apoptosis-related proteins, indicating enhanced cell death.

Conclusions:

  • Polymyxin B-induced nephrotoxicity is mediated by oxidative stress through the inhibition of the Nrf2/NQO1 pathway.
  • Polymyxin B promotes kidney cell apoptosis, contributing to renal injury.
  • These findings provide molecular insights into Polymyxin B nephrotoxicity, potentially guiding therapeutic strategies.
Keywords:
Nrf2/NQO1 pathwayapoptosisnephrotoxicityoxidative stresspolymyxin B

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