Chronic COX Inhibition Reduces Diabetes-Induced Hyperfiltration, Proteinuria, and Renal Pathological Markers in 36-Week B6-Ins2Akita Mice

BACKGROUND/AIMS: 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. CONCLUSION: 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.