title: Chronic COX inhibition reduces diabetes-induced hyperfiltration, proteinuria, and renal pathological markers in 36-week B6-Ins2(Akita) mice.
abstract: OBJECTIVE
  The widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) and the sizeable impact of diabetes on the development of end-stage renal disease substantiate the need to determine their effect on the evolution of diabetic nephropathy (DN). We hypothesized that chronic ibuprofen and NS-398 will differentially affect many aspects of DN in B6-Ins2(Akita) mice, including glomerular filtration rate (GFR), growth, and fibrosis.
  
  
  METHODS
  B6-Ins2(Akita) and wild-type mice were separated into six groups. At 20 weeks of age, NSAIDs (1 mg/kg/day) were added to the drinking water daily. At 36 weeks indicators of renal function and DN were examined.
  
  
  RESULTS
  Urinary PGE(2), PGEM, TXB(2), and 6-keto-PGF(1)alpha were increased in diabetics, and reduced by NSAIDs. Regional differences in cyclooxygenases were observed. Diabetics displayed hyperglycemia, albuminuria, and increased kidney/body weights, glomerular diameters, and FITC-inulin clearance. NSAIDs did not affect growth, but albuminuria and FITC-inulin clearance were reduced. Also, p27 and fibronectin were increased in diabetics and attenuated by ibuprofen.
  
  
  CONCLUSIONS
  NSAIDs reduced diabetic change: GFR, albuminuria, p27, and fibronectin. The effects of ibuprofen are similar if not more beneficial than COX-2 inhibition by NS-398. This study has clinical relevance for diabetics prior to overt nephropathy. Future studies should reveal the effects of NSAIDs in a more severe disease environment.
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ont., Canada.
authors.forename: Rania
authors.initials: R
authors.lastname: Nasrallah
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hébert
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D003404:Creatinine / Q000652:urine; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009578:Nitrobenzenes / Q000494:pharmacology*; D009929:Organ Size; D011453:Prostaglandins / Q000652:urine; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D005353:Fibronectins; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003404:Creatinine; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D007052:Ibuprofen