Cyclooxygenase 2 inhibition slows disease progression and improves the altered renal lipid mediator profile in the Pkd2WS25/− mouse model of autosomal dominant polycystic kidney disease

Abstract

Increased levels of cyclooxygenase (COX) derived oxylipins is the earliest and most consistent alteration in the renal oxylipin profile in diverse models of cystic kidney diseases. Therefore, we examined whether a COX2 inhibitor would reduce disease progression in the Pkd2WS25/- mouse model of autosomal dominant polycystic kidney disease (ADPKD). Weanling normal and diseased male Pkd2 mice were provided diets that provided 0 or 50mg celecoxib/kg body weight/day, for 13weeks. Renal disease and function were assessed by histomorphometric analysis of renal cysts and measurement of serum creatinine and urea nitrogen (SUN) levels. Targeted lipidomic analysis of renal oxylipins was performed by HPLC-MS/MS. Diseased mice had significant cyst involvement and reduced renal function as indicated by elevated serum creatinine and SUN. Celecoxib reduced cyst area by 48%, cyst volume by 70%, and serum creatinine and SUN by 20% and 16%, respectively. Consistent with our previous studies, 8 of the 11 COX derived oxylipins were higher in diseased kidneys. In addition, 24 of 33 lipoxygenase (LOX) derived oxylipins and 7 of 16 cytochrome P450 (CYP) derived oxylipins were lower in diseased kidneys. Celecoxib reduced total and five of the eight individual elevated COX oxylipins and increased 5 of 24 LOX and 5 of 7 CYP oxylipins that were reduced by disease. COX2 inhibition ameliorates disease progression, improves renal function and improves the altered oxylipins in Pkd2 mice. This represents a potential new approach for treatment of ADPKD, a disorder for which no effective treatment currently exists.