title: Celecoxib modifies glomerular basement membrane, mesangium and podocytes in OVE26 mice, but ibuprofen is more detrimental.
abstract: The role of COXs/PGs (cyclo-oxygenases/prostaglandins) in diabetic kidneys remains unclear. NSAIDs (non-steroidal anti-inflammatory drugs) that inhibit COXs/PGs are known for their renal toxicity, and COX-2 inhibitors worsen cardiovascular outcomes in susceptible individuals. Given the renal controversies concerning COX-2 inhibitors, we compared the effect of chronic NSAIDs (non-selective, ibuprofen; COX-2-selective, celecoxib) on diabetic kidneys in OVE26 mice from 8 weeks of age. Systolic BPs (blood pressures) were increased by NSAIDs in diabetic mice at 20 weeks, but were unchanged at 32 weeks. Although NSAIDs further increased diabetic kidney/body weight ratios, they did not affect albuminuria. Mesangial matrix was increased 2-fold by celecoxib but not ibuprofen. Electron microscopy revealed that NSAIDs reduced GBM (glomerular basement membrane) thickness and slit pore diameters. Although diabetics had increased glomerular diameters and reduced foot process densities, these were unaltered by NSAIDs. Celecoxib does not exacerbate the diabetic state, but PG inhibition may contribute to disease progression by modifying the GBM, mesangial area and podocyte structure in OVE26 mice. Despite these findings, celecoxib remains safer than a similar dose of ibuprofen. The present study substantiates the need to more closely consider selective COX-2 inhibitors such as celecoxib as alternatives to non-selective NSAIDs for therapeutic management in a setting of chronic kidney disease.
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada K1H 8M5.
authors.forename: Rania
authors.initials: R
authors.lastname: Nasrallah
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.forename: Jacob
authors.initials: J
authors.lastname: Karsh
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hébert
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure / Q000187:drug effects; D000068579:Celecoxib; D003404:Creatinine / Q000097:blood; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000473:pathology*; D050533:Glomerular Basement Membrane / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000473:pathology; D007052:Ibuprofen / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D011453:Prostaglandins / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000418:Albumins; D001786:Blood Glucose; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D003404:Creatinine; D000068579:Celecoxib; D007052:Ibuprofen