Role of heme oxygenase-1 in polymyxin B-induced nephrotoxicity in rats.
Polymyxin B (PMB) is a cationic polypeptide antibiotic with activity against multidrug-resistant Gram-negative bacteria. PMB-induced nephrotoxicity consists of direct toxicity to the renal tubules and the release of reactive oxygen species (ROS) with oxidative damage. This study evaluated the nephroprotective effect of heme oxygenase-1 (HO-1) against PMB-induced nephrotoxicity in rats. Adult male Wistar rats, weighing 286 ± 12 g, were treated intraperitoneally once a day for 5 days with saline, hemin (HO-1 inducer; 10 mg/kg), zinc protoporphyrin (ZnPP) (HO-1 inhibitor; 50 μmol/kg, administered before PMB on day 5), PMB (4 mg/kg), PMB plus hemin, and PMB plus ZnPP. Renal function (creatinine clearance, Jaffe method), urinary peroxides (ferrous oxidation of xylenol orange version 2 [FOX-2]), urinary thiobarbituric acid-reactive substances (TBARS), renal tissue thiols, catalase activity, and renal tissue histology were analyzed. The results showed that PMB reduced creatinine clearance (P < 0.05), with an increase in urinary peroxides and TBARS. The PMB toxicity caused a reduction in catalase activity and thiols (P < 0.05). Hemin attenuated PMB nephrotoxicity by increasing the catalase antioxidant activity (P < 0.05). The combination of PMB and ZnPP incremented the fractional interstitial area of renal tissue (P < 0.05), and acute tubular necrosis in the cortex area was also observed. This is the first study demonstrating the protective effect of HO-1 against PMB-induced nephrotoxicity.
Experimental Laboratory of Animal Models (LEMA), School of Nursing, University of Sao Paulo, São Paulo, Brazil.
Cassiane
C
Dezoti Fonseca
Mirian
M
Watanabe
Maria de Fátima Fernandes
Mde F
Vattimo
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011112:Polymyxin B / Q000009:adverse effects*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000900:Anti-Bacterial Agents; D011524:Protoporphyrins; D026361:Reactive Nitrogen Species; D013438:Sulfhydryl Compounds; D017392:Thiobarbituric Acid Reactive Substances; C017803:zinc protoporphyrin; D006427:Hemin; D002374:Catalase; D051547:Heme Oxygenase-1; D011112:Polymyxin B