Tanaka Tamami, Noiri Eisei, Yamamoto Tokunori, Sugaya Takeshi, Negishi Kousuke, Maeda Rui, Nakamura Kazuo, Portilla Didier, Goto Momokazu, Fujita Toshiro
Department of Nephrology and Endocrinology, Tokyo University Hospital, Tokyo, Japan.
Nephron Exp Nephrol. 2008;108(1):e19-26. doi: 10.1159/000112912. Epub 2008 Jan 8.
BACKGROUND/AIM: A strong demand exists for the development of sensitive biomarkers in the nephrology field. We propose urinary human L-type fatty acid binding protein (L-FABP) as an earlier biomarker to detect the outcome of chronic renal injury induced by cyclooxygenase (COX) inhibitors using human L-FABP transgenic mice.
After consuming a low-sodium diet for 2 weeks, transgenic mice were administered meloxicam or celecoxib with the low-sodium diet. Mice were sacrificed 2 days and 4 weeks after starting COX inhibitors, and urine was collected 24 and 48 h and 1, 2, 3, and 4 weeks after starting COX inhibitors. Celecoxib-treated mice were divided into responders or nonresponders according to urinary L-FABP levels, and histology, urinary L-FABP and peritubular capillary blood flow were evaluated.
Meloxicam-treated mice showed a higher blood pressure than control mice. Urinary L-FABP was significantly increased in COX inhibitor-treated mice. Peritubular capillary blood flow in all meloxicam-treated mice and in some celecoxib-treated mice was significantly decreased. Although blood urea nitrogen was not increased, interstitial fibrosis and macrophage infiltration were revealed, especially in meloxicam-treated mice. Responders showed an increase of fibrotic areas and correlations between urinary L-FABP and peritubular capillary blood flow.
Urinary L-FABP is capable of revealing chronic renal injury induced by COX inhibitors.
背景/目的：肾脏病领域对开发敏感的生物标志物有强烈需求。我们提出将尿人L型脂肪酸结合蛋白（L-FABP）作为一种早期生物标志物，利用人L-FABP转基因小鼠来检测环氧化酶（COX）抑制剂所致慢性肾损伤的结果。
转基因小鼠在食用低钠饮食2周后，继续给予低钠饮食并同时服用美洛昔康或塞来昔布。在开始给予COX抑制剂后2天和4周处死小鼠，并在开始给予COX抑制剂后24小时和48小时以及1、2、3和4周收集尿液。根据尿L-FABP水平将塞来昔布治疗的小鼠分为反应者或无反应者，并对组织学、尿L-FABP和肾小管周围毛细血管血流进行评估。
美洛昔康治疗的小鼠血压高于对照小鼠。COX抑制剂治疗的小鼠尿L-FABP显著增加。所有美洛昔康治疗的小鼠以及一些塞来昔布治疗的小鼠肾小管周围毛细血管血流显著减少。虽然血尿素氮没有升高，但出现了间质纤维化和巨噬细胞浸润，尤其是在美洛昔康治疗的小鼠中。反应者显示纤维化区域增加，且尿L-FABP与肾小管周围毛细血管血流之间存在相关性。
尿L-FABP能够揭示COX抑制剂所致的慢性肾损伤。
