Evidence suggesting a role for hydroxyl radical in glycerol-induced acute renal failure

Reactive oxygen metabolites, in particular hydroxyl radical, have been shown to be important mediators of tissue injury in several models of acute renal failure. The aim of the present study was to examine the role of hydroxyl radical in glycerol-induced acute renal failure, a model for myoglobinuric renal injury. Rats injected with glycerol alone (8 mg/kg im following dehydration for 24 h) developed significant renal failure compared with dehydrated controls. Rats treated with glycerol and a hydroxyl radical scavenger, dimethylthiourea (DMTU), had significantly lower blood urea nitrogen (BUN) and creatinine. In contrast, urea, which is chemically similar to DMTU but is not a hydroxyl radical scavenger, provided no protection. In addition, DMTU prevented the glycerol-induced rise in renal cortical malondialdehyde content (a measure of lipid peroxidation that serves as a marker of free radical-mediated tissue injury). A second hydroxyl radical scavenger, sodium benzoate, had a similar protective effect on renal function (as measured by both BUN and creatinine). Because the generation of hydroxyl radical in biological systems requires the presence of a trace metal such as iron, we also examined the effect of the iron chelator, deferoxamine on glycerol-induced renal failure. Deferoxamine was also protective. The interventional agents were also associated with a marked reduction in histological evidence of renal damage. The protective effects of two hydroxyl radical scavengers as well as an iron chelator implicate a role for hydroxyl radical in glycerol-induced acute renal failure.

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Evidence suggesting a role for hydroxyl radical in passive Heymann nephritis in rats

AJP Renal Physiology ◽

10.1152/ajprenal.1988.254.3.f337 ◽

1988 ◽

Vol 254 (3) ◽

pp. F337-F344 ◽

Cited By ~ 6

Author(s):

S. V. Shah

Keyword(s):

Hydroxyl Radical ◽

Marked Reduction ◽

Iron Chelator ◽

Radical Scavenger ◽

Reactive Oxygen Metabolites ◽

Heymann Nephritis ◽

Hydroxyl Radical Scavenger ◽

And Control ◽

Complement Deposition ◽

Oxygen Metabolites

We examined the effect of scavengers of reactive oxygen metabolites on proteinuria in the passive Heymann nephritis model of membranous nephropathy. Passive Heymann nephritis was induced by a single intravenous injection of anti-Fx1A IgG in a dose of 10 mg/100 g body weight. Superoxide dismutase, a scavenger of superoxide or catalase which destroys hydrogen peroxide, did not affect the proteinuria. In contrast, dimethylthiourea (DMTU, 500 mg/kg followed by 125 mg/kg ip twice a day), a scavenger of hydroxyl radical, markedly reduced the proteinuria (day 5: anti-Fx1A 53 +/- 13, n = 18; anti-Fx1A + DMTU, 21 +/- 6 mg/24 h, n = 15, P less than 0.001). Experiments with 125I-labeled anti-Fx1A antibody demonstrated that DMTU did not affect the amount of antibody deposited in the kidney. Semiquantitative estimation of IgG and complement deposition in the kidney showed no differences between the DMTU-treated and control rats. A second hydroxyl radical scavenger, sodium benzoate (150 mg/kg ip twice a day), also resulted in marked reduction in proteinuria (day 5: anti-Fx1A 56 +/- 7, n = 9; anti-Fx1A + benzoate, 14 +/- 4 mg/24 h, n = 8, P less than 0.01). Because of the participation of iron in biological systems to generate hydroxyl radical, we also examined the effect of deferoxamine (DFO, 35 mg/day), an iron chelator, on the anti-Fx1A-induced proteinuria. There was a significant reduction in proteinuria in rats treated concurrently with DFO (day 5: anti-Fx1A 67 +/- 13, n = 15; anti-Fx1A + DFO, 29 +/- 4 mg/24 h, n = 15, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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Oestrogen protects against ischaemic acute renal failure in rats by suppressing renal endothelin-1 overproduction

Clinical Science ◽

10.1042/cs103s434s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 434S-437S ◽

Cited By ~ 27

Author(s):

Masanori TAKAOKA ◽

Mikihiro YUBA ◽

Toshihide FUJII ◽

Mamoru OHKITA ◽

Yasuo MATSUMURA

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Renal Dysfunction ◽

Tissue Injury ◽

Male Rats ◽

Left Renal Artery ◽

Protective Effects ◽

Endothelin 1 ◽

Ischaemia Reperfusion

We investigated whether the treatment with 17β-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17β-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17β-oestradiol (20 or 100µg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17β-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17β-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.

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Gentamicin-induced mobilization of iron from renal cortical mitochondria

AJP Renal Physiology ◽

10.1152/ajprenal.1993.265.3.f435 ◽

1993 ◽

Vol 265 (3) ◽

pp. F435-F439 ◽

Cited By ~ 6

Author(s):

N. Ueda ◽

B. Guidet ◽

S. V. Shah

Keyword(s):

Hydrogen Peroxide ◽

Hydroxyl Radical ◽

Tissue Injury ◽

Iron Chelator ◽

Iron Release ◽

Radical Scavengers ◽

Iron Mobilization ◽

No Formation ◽

Hydroxyl Radical Scavengers ◽

Dose Dependent

Iron, presumably by participating in generation of hydroxyl radical or other oxidant species or initiation of lipid peroxidation, has been shown to play an important role in several models of tissue injury, including acute renal failure induced by the antibiotic gentamicin. However, the sources of iron remain unknown. Rat renal mitochondria incubated at 37 degrees C with gentamicin resulted in a time- (15-60 min) and a dose-dependent (0.01-5 mM) iron release as measured by formation of iron-bathophenanthroline sulfonate complex FeII-(BPS)3 [at 60 min, control: 1.2 +/- 0.1 nmol/mg protein, n = 7; gentamicin (5 mM): 5.1 +/- 0.4 nmol/mg protein, n = 7]. No formation of FeII(BPS)3 complex was detected in the absence of mitochondria or when incubations were carried out at 0 degrees C. Similar results were obtained when 2,2'-dipyridyl, another iron chelator, was used for measurement of iron release. On the basis on our previous study that gentamicin enhances generation of hydrogen peroxide by renal cortical mitochondria, we examined whether effect of gentamicin on iron release is mediated by hydrogen peroxide. Catalase (which decomposes hydrogen peroxide), but not heat-inactivated catalase, as well as pyruvate, a potent scavenger of hydrogen peroxide, prevented gentamicin-induced iron mobilization. Superoxide dismutase, a scavenger of superoxide anion, or hydroxyl radical scavengers (dimethylthiourea or sodium benzoate) had no effect. Taken together, the data with scavengers indicate that gentamicin-induced iron mobilization from mitochondria is mediated by hydrogen peroxide.

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Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure

AJP Renal Physiology ◽

10.1152/ajprenal.1989.256.3.f446 ◽

1989 ◽

Vol 256 (3) ◽

pp. F446-F455 ◽

Cited By ~ 5

Author(s):

R. A. Zager ◽

L. M. Gamelin

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Renal Damage ◽

Iron Chelation ◽

Proximal Tubular Cell ◽

Radical Scavenger ◽

Heme Uptake ◽

Hydroxyl Radical Scavenger ◽

Proximal Tubular ◽

Hemoglobin Production

To evaluate mechanisms in hemoglobinuric acute renal failure (ARF) rats were infused with hemoglobin under aciduric or alkalinuric conditions. Aciduric rats developed azotemia, distal heme casts, and proximal tubular cell (PTC) necrosis, whereas alkalinuric rats developed no renal damage. Aciduria converted hemoglobin to met-hemoglobin, which precipitated, forming distal casts and inducing ARF. Hematin formation was not observed. The importance of met-hemoglobin production was indicated by its greater toxicity than hemoglobin during aciduria and by its ability to induce ARF even under alkalinuric conditions. A link between obstructing casts and PTC necrosis was identified; tubular obstruction induced by various mechanisms (met-hemoglobin casts; ureteral ligation; ischemic ARF) increased PTC hemoglobin uptake, producing lysosomal overload (giant endolysosomes) and PTC necrosis. This worsened ischemic ARF despite an otherwise subtoxic hemoglobin dose being used that had no discernible acute renal vasoconstrictive effect. Iron chelation (deferoxamine)/hydroxyl radical scavenger (Na benzoate) therapy did not mitigate this exacerbation of ischemic injury, suggesting a nonoxidant mechanism. We conclude that H is nephrotoxic, particularly when intratubular obstruction facilitates PTC heme uptake. Thus aciduria-induced met-hemoglobin cast formation and concomitant ischemic renal injury predispose to its nephrotoxic effect.

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Contribution of Oxidative Damage to Antimicrobial Lethality

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01087-08 ◽

2009 ◽

Vol 53 (4) ◽

pp. 1395-1402 ◽

Cited By ~ 129

Author(s):

Xiuhong Wang ◽

Xilin Zhao

Keyword(s):

Oxidative Stress ◽

Escherichia Coli ◽

Hydroxyl Radical ◽

Hydroxyl Radicals ◽

Fenton Reaction ◽

Iron Chelator ◽

Radical Scavenger ◽

Alkyl Hydroperoxide ◽

Hydroxyl Radical Scavenger ◽

Rapid Conversion

ABSTRACT A potential pathway linking hydroxyl radicals to antimicrobial lethality was examined by using mutational and chemical perturbations of Escherichia coli. Deficiencies of sodA or sodB had no effect on norfloxacin lethality; however, the absence of both genes together reduced lethal activity, consistent with rapid conversion of excessive superoxide to hydrogen peroxide contributing to quinolone lethality. Norfloxacin was more lethal with a mutant deficient in katG than with its isogenic parent, suggesting that detoxification of peroxide to water normally reduces quinolone lethality. An iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) reduced the lethal activity of norfloxacin, indicating that norfloxacin-stimulated accumulation of peroxide affects lethal activity via hydroxyl radicals generated through the Fenton reaction. Ampicillin and kanamycin, antibacterials unrelated to fluoroquinolones, displayed behavior similar to that of norfloxacin except that these two agents showed hyperlethality with an ahpC (alkyl hydroperoxide reductase) mutant rather than with a katG mutant. Collectively, these data are consistent with antimicrobial stress increasing the production of superoxide, which then undergoes dismutation to peroxide, from which a highly toxic hydroxyl radical is generated. Hydroxyl radicals then enhance antimicrobial lethality, as suggested by earlier work. Such findings indicate that oxidative stress networks may provide targets for antimicrobial potentiation.

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Reactions of NO2 and nitrite ion with organic radicals

Canadian Journal of Chemistry ◽

10.1139/v84-313 ◽

1984 ◽

Vol 62 (9) ◽

pp. 1831-1834 ◽

Cited By ~ 8

Author(s):

Allen John Elliot ◽

Anita Sandra Simsons

Keyword(s):

Hydroxyl Radical ◽

Organic Radicals ◽

Radical Scavenger ◽

Radical Scavengers ◽

Nitrite Ion ◽

Aqueous Sodium ◽

Hydroxyl Radical Scavenger ◽

Hydroxyalkyl Radicals ◽

Hydroxyl Radical Scavengers ◽

Nitrate Solutions

When deoxygenated aqueous sodium nitrate solutions containing an alcohol as a hydroxyl radical scavenger are irradiated, [Formula: see text] depends on the fraction of [Formula: see text] which forms 1-hydroxyalkyl radicals. This arises because [Formula: see text] is not reduced to nitrite by 2- or 3-hydroxyalkyl radicals.Helium- and N2O-saturated sodium nitrite solutions containing different organic hydroxyl radical scavengers were irradiated. Measurements of [Formula: see text] showed that the radicals, ĊH2OH and ĊH2C(CH3)2OH, do not react with the nitrite ion as rapidly as [Formula: see text] and (CH,)2ĊOH. With the latter two radicals, nitric oxide is probably formed from the reaction with the nitrite ion.

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