A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats
A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats
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DOI：
10.1046/j.1523-1755.2000.00093.x
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发表时间：
2000-06-01
影响因子：
19.6
通讯作者：
Harris, RC
中科院分区：
文献类型：
--
作者：
Wang, JL;Cheng, HF;Harris, RC
背景。我们之前已经表明，成年大鼠肾皮质中环氧合酶-2 (COX-2) 表达较低，但在肾次全消融后，致密斑/皮质厚升肢和肾小球足细胞中表达增加。方法。为了评估 COX-2 表达增加的功能后果，对雄性大鼠进行次全肾消融，并将其分为四组：（I）用选择性 COX-2 抑制剂 SC58236 治疗，（2）用载体治疗，（3）用血管紧张素转换酶抑制剂依那普利治疗，以及（4）用依那普利 + SC58236 治疗。消融后第三天开始给药，持续6至10周。 结果。消融后一周内，接受载体治疗的大鼠出现高血压。尽管依那普利单独使用或与 COX-2 抑制剂联合使用可显着降低血压，但单独使用 SC58236 并不能显着改变消融引起的高血压。然而，接受 SC58236 治疗的动物在消融后六周时表现出的蛋白尿水平与依那普利观察到的蛋白尿水平相当（载体，47 +/- 4；依那普利，27 +/- 2；SC58236，30 +/- 2 mg/天；N = 7，P < 0.01，每组与载体相比），并且持续的 SC58236 治疗导致蛋白尿持续降低。肾消融后 10 周出现蛋白尿（媒介物，77 +/- 4；SC58236，50 +/- 4 mg/天；N = 6，P < 0.01）。 SC58236 治疗还显着降低了第 10 周时表现出节段性或整体硬化的肾小球百分比（32.6 +/- 7.8% 对比 10.9 +/- 2.8%，N = 6，P < 0.03）。此外，SC58236 治疗部分抑制了转化生长因子-β 1 mRNA 表达的增加以及胶原蛋白 III 和胶原蛋白 IV mRNA 表达的增加。结论。这些研究表明，用特定的COX-2抑制剂进行长期治疗可能会延缓进行性肾损伤的进展，并表明此类化合物可以与血管紧张素转换酶抑制剂联合使用。需要进一步的研究来确定 COX-2 抑制具有肾脏保护作用的机制。
Background. We have previously shown that cyclooxygenase-2 (COX-2) expression is low in the renal cortex of adult rats, but is increased in macula densa/cortical thick ascending limb and in glomerular podocytes after subtotal renal ablation.Methods. To evaluate the functional consequences of this increased COX-2 expression, male rats were subjected to subtotal renal ablation and divided into four groups: (I) treatment with the selective COX-2 inhibitor SC58236, (2) treatment with vehicle, (3) treatment with the angiotensin-converting enzyme inhibitor enalapril, and (4) treatment with enalapril + SC58236. The administration of drugs was begun on the third day after ablation and continued for 6 to 10 weeks.Results. Within one week after ablation, vehicle-treated rats developed hypertension. Although enalapril led to significant reductions in blood pressure, either alone or in combination with the COX-2 inhibitor, SC58236 alone did not significantly alter ablation-induced hypertension. However, the SC58236-treated animals exhibited levels of proteinuria at six weeks after ablation that were comparable to those seen with enalapril (vehicle, 47 +/- 4;enalapril, 27 +/- 2; SC58236, 30 +/- 2 mg/day; N = 7, P < 0.01, each group compared with vehicle), and continued SC58236 treatment led to persistent reductions in proteinuria at 10 weeks after renal ablation (vehicle, 77 +/- 4; SC58236, 50 +/- 4 mg/day; N = 6, P < 0.01). SC58236 treatment also significantly reduced the percentage of glomeruli exhibiting segmental or global sclerosis at 10 weeks (32.6 +/- 7.8% vs. 10.9 +/- 2.8%, N = 6, P < 0.03). Furthermore, SC58236 treatment partially inhibited increases in transforming growth factor-beta 1 mRNA expression and increases in collagen III and collagen IV mRNA expression.Conclusions. These studies indicate that chronic treatment with a specific COX-2 inhibitor may retard the progression of progressive renal injury, and suggest that such compounds can be used in combination with angiotensin-converting enzyme inhibitors. Further studies are required to determine the mechanism by which COX-2 inhibition is renoprotective.