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Role of heme oxygenase-1 in polymyxin B-induced nephrotoxicity in rats

Cassiane Dezoti Fonseca1, Mirian Watanabe, Maria de Fátima Fernandes Vattimo

  • 1Experimental Laboratory of Animal Models (LEMA), School of Nursing, University of Sao Paulo, São Paulo, Brazil.

Antimicrobial Agents and Chemotherapy
|July 18, 2012
PubMed

Insights

Heme oxygenase-1 (HO-1) protects against Polymyxin B (PMB) induced kidney damage by reducing oxidative stress. This study shows HO-1 induction by hemin offers nephroprotection against PMB toxicity in rats.

Area of Science:

  • Nephrology
  • Pharmacology
  • Toxicology

Background:

  • Polymyxin B (PMB) is crucial for treating multidrug-resistant Gram-negative infections.
  • PMB-induced nephrotoxicity involves direct renal tubule damage and oxidative stress via reactive oxygen species (ROS).
  • Heme oxygenase-1 (HO-1) is an endogenous antioxidant enzyme with potential protective roles.

Purpose of the Study:

  • To investigate the nephroprotective effect of heme oxygenase-1 (HO-1) against Polymyxin B (PMB)-induced nephrotoxicity in a rat model.
  • To elucidate the role of HO-1 induction and inhibition in modulating PMB-induced renal damage and oxidative stress.

Main Methods:

  • Adult male Wistar rats were administered saline, hemin (HO-1 inducer), zinc protoporphyrin (ZnPP, HO-1 inhibitor), PMB, or combinations thereof.
  • Evaluated renal function via creatinine clearance and oxidative stress markers including urinary peroxides (FOX-2) and TBARS.
  • Assessed renal tissue antioxidant capacity (catalase activity, thiols) and performed histological analysis for tubular injury.

Main Results:

  • PMB administration significantly reduced creatinine clearance and increased oxidative stress markers (urinary peroxides, TBARS).
  • PMB treatment decreased renal catalase activity and thiol levels, indicating oxidative damage.
  • Hemin administration attenuated PMB nephrotoxicity by enhancing catalase activity.
  • Co-administration of PMB and ZnPP exacerbated renal interstitial fibrosis and acute tubular necrosis.

Conclusions:

  • Heme oxygenase-1 (HO-1) exhibits a significant nephroprotective effect against Polymyxin B (PMB)-induced kidney injury in rats.
  • HO-1 induction via hemin mitigates PMB-induced oxidative stress and renal dysfunction.
  • This study provides the first evidence for HO-1's protective role in combating PMB nephrotoxicity.

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