title: An evaluation of antioxidant effects on recovery from postischemic acute renal failure.
abstract: Xanthine oxidase (XO) activity and hydroxyl radical (.OH) formation are widely proposed mediators of renal reperfusion injury, potentially altering the severity of, and recovery from, postischemic acute renal failure. The goal of this study was to ascertain whether combination XO inhibitor (oxypurinol) and .OH scavenger (Na benzoate) therapy, given at the time of renal ischemia, alters the extent of: (1) tubular necrosis and filtration failure; (2) DNA fragmentation/apoptosis (assessed in situ by terminal deoxynucleotidyl transferase reactivity); (3) early tubular regenerative responses (proliferating cell nuclear antigen expression; (3H)thymidine incorporation); and (4) the rate and/or degree of functional and morphologic repair. The effects of XO inhibition, .OH scavengers, and "catalytic" iron (FeSO4) on human proximal tubular cell proliferation in vitro were also assessed with a newly established cell line (HK-2). Male Sprague-Dawley rats were subjected to 35 min of bilateral renal arterial occlusion with or without oxypurinol/benzoate therapy. These agents did not alter the extent of tubular necrosis or filtration failure, proliferating cell nuclear antigen expression or thymidine incorporation, or the rate/extent of renal functional/morphologic repair. DNA fragmentation did not precede tubular necrosis, and it was unaffected by antioxidant therapy. By 5 days postischemia, both treatment groups demonstrated regenerating epithelial fronds that protruded into the lumina. These structures contained terminal deoxynucleotidyl transferase-reactive, but morphologically intact, cells, suggesting the presence of apoptosis. Oxypurinol and .OH scavengers (benzoate; dimethylthiourea) suppressed in vitro tubular cell proliferation; conversely, catalytic Fe had a growth-stimulatory effect. These results suggest that: (1) XO inhibition/.OH scavenger therapy has no discernible net effect on postischemic acute renal failure; (2) DNA fragmentation does not precede tubular necrosis, suggesting that it is not a primary mediator of ischemic cell death; and (3) antioxidants can be antiproliferative for human tubular cells, possibly mitigating their potential beneficial effects.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
authors.forename: R A
authors.initials: RA
authors.lastname: Zager
authors.forename: S M
authors.initials: SM
authors.lastname: Fuerstenberg
authors.forename: P H
authors.initials: PH
authors.lastname: Baehr
authors.forename: D
authors.initials: D
authors.lastname: Myerson
authors.forename: B
authors.initials: B
authors.lastname: Torok-Storb
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D019817:Benzoic Acid; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000032:analysis; D016166:Free Radical Scavengers; D006801:Humans; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply* / Q000502:physiology; D007683:Kidney Tubular Necrosis, Acute / Q000188:drug therapy / Q000517:prevention & control*; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis; D010117:Oxypurinol / Q000494:pharmacology / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000975:Antioxidants; D001565:Benzoates; D016166:Free Radical Scavengers; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D019817:Benzoic Acid; D014969:Xanthine Oxidase; D004253:DNA Nucleotidylexotransferase; D010117:Oxypurinol