Disruption of cyclooxygenase type 2 exacerbates the progression of oxidative stress during obstructive nephropathy (1134.2)

Abstract

Renal oxidative stress is increased in response to ureteral obstruction. In vitro, COX‐2 activity contributes to antioxidative protection. Here, we test the hypothesis that COX‐2 activity counters oxidative stress in an in vivo setting of obstructive nephropathy. The progression of renal oxidative stress was investigated in COX‐2‐/‐ and WT mice subjected to 3 days of unilateral ureteral obstruction (UUO).Following UUO, kidney weight and functional parameters were analysed. Using immunoblot analysis, we examined the oxidative stress marker, heme oxygenase‐1 (HO‐1), antioxidant enzymes, superoxide dismutase 1 and 2 (SOD1 and ‐2), and caspase 3 in renal cortex and inner medulla (IM).Plasma creatinine was increased in response to UUO, however, COX‐2‐/‐ had more increased plasma creatinine compared to WT. COX‐2 mRNA level was increased in WT mice subjected to UUO and undetectable in COX‐2‐/‐ mice. HO‐1 protein abundance increased in response to UUO and was further increased in COX‐2‐/‐ mice. Both SOD1 and SOD2 protein levels were downregulated in IM and cortex in WT mice after UUO. COX‐2 knockout prevented downregulation of SOD2 in both cortex and IM whereas SOD1 reduction was only attenuated in cortex. Cortical caspase 3 was increased in response to UUO, and further increased in COX‐2‐/‐ mice.In summary, disruption of COX‐2 exacerbates oxidative stress and increases apoptosis markers in response to obstruction.