title: Disruption of cyclooxygenase type 2 exacerbates apoptosis and renal damage during obstructive nephropathy.
abstract: Renal oxidative stress is increased in response to ureteral obstruction. In vitro, cyclooxygenase (COX)-2 activity contributes to protection against oxidants. In the present study, we tested the hypothesis that COX-2 activity counters oxidative stress and apoptosis in an in vivo model of obstructive nephropathy. Renal oxidative stress markers, antioxidant enzymes, and markers of tubular injury, tubular dilation, and apoptosis were investigated in COX-2 knockout (COX-2(-/-)) and wild-type (WT) mice subjected to 3 or 7 days of unilateral ureteral obstruction (UUO). In a separate series, WT sham-operated and UUO mice were treated with a selective COX-2 inhibitor, parecoxib. COX-2 increased in response to UUO; the oxidative stress markers 4-hydroxynonenal and nitrotyrosine protein residues increased in kidney tissue with no genotype difference after UUO, whereas the antioxidant enzymes heme oxygenase-1 and SOD2 displayed higher levels in COX-2(-/-) mice. Tubular injury was aggravated by COX-2 deletion, as measured by tubular dilatation, an increase in kidney injury molecule-1, cortical caspase-3 content, and apoptosis index. In conclusion, COX-2 is necessary to protect against tubular injury and apoptosis after UUO but not necessary to protect against oxidative stress. COX-2 is not likely to directly regulate antioxidant enzymes heme oxygenase-1 and SOD in the kidney.
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark;
authors.forename: Line
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark; Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Madsen
authors.affiliation: Department of Pathology, Aarhus University Hospital, Aarhus, Denmark; and.
authors.forename: Søren
authors.initials: S
authors.lastname: Krag
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark;
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
authors.affiliation: Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark;
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; rn@clin.au.dk.
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D014517:Ureteral Obstruction / Q000201:enzymology* / Q000473:pathology
chemical_list: D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: apoptosis; cyclooxygenase-2; oxidative stress; unilateral ureteral obstruction