Nasrallah Rania, Robertson Susan J, Hébert Richard L
Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ont., Canada.
Am J Nephrol. 2009;30(4):346-53. doi: 10.1159/000229304. Epub 2009 Jul 17.
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.
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.
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.
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.
背景/目的：非甾体抗炎药（NSAIDs）的广泛使用以及糖尿病对终末期肾病发展的重大影响，证实了确定其对糖尿病肾病（DN）进展影响的必要性。我们假设慢性给予布洛芬和NS-398会对B6-Ins2（Akita）小鼠DN的多个方面产生不同影响，包括肾小球滤过率（GFR）、生长和纤维化。
将B6-Ins2（Akita）小鼠和野生型小鼠分为六组。在20周龄时，每天在饮水中添加NSAIDs（1毫克/千克/天）。在36周时检查肾功能和DN指标。
糖尿病小鼠尿中前列腺素E2（PGE2）、前列腺素EM（PGEM）、血栓素B2（TXB2）和6-酮-前列腺素F1α（6-keto-PGF1α）升高，NSAIDs使其降低。观察到环氧化酶存在区域差异。糖尿病小鼠出现高血糖、蛋白尿，肾/体重、肾小球直径和异硫氰酸荧光素-菊粉清除率增加。NSAIDs不影响生长，但可降低蛋白尿和异硫氰酸荧光素-菊粉清除率。此外，糖尿病小鼠中p27和纤连蛋白增加，布洛芬可使其减弱。
NSAIDs减轻了糖尿病相关变化：GFR、蛋白尿、p27和纤连蛋白。布洛芬的作用即使不比NS-398抑制COX-2更有益，也与之相似。本研究对显性肾病之前的糖尿病患者具有临床意义。未来研究应揭示NSAIDs在更严重疾病环境中的作用。
