Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension
Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension
复制标题
DOI：
10.1046/j.1523-1755.2002.00520.x
复制
发表时间：
2002-09-01
影响因子：
19.6
通讯作者：
Harris, RC
中科院分区：
文献类型：
--
作者：
Cheng, HF;Wang, CJ;Harris, RC
背景。我们之前报道过肾皮质环氧化酶（COX-2）表达在肾大部切除术后增加，选择性COX-2抑制剂SC58236的慢性治疗可以减少蛋白尿并延缓肾小球硬化的发展。本研究旨在研究COX-2抑制对糖尿病肾病模型的影响。将大鼠分为三组：对照组、糖尿病组（链脲佐菌素诱导的合并DOCA/盐性高血压的糖尿病动物；右肾切除术和DOCA治疗组）和治疗组（对一部分糖尿病/DOCA/盐性大鼠给予选择性COX-2抑制剂SC58236）。给予胰岛素维持血糖在200 ~ 300 mg/dL范围内。两组糖尿病患者的收缩压在一周内升高，并保持升高直至6周牺牲（对照组，108 +/- 2毫米汞柱；糖尿病组，158 +/- 4毫米汞柱；治疗组，156 +/- 7毫米汞柱）。6周时测量，糖尿病大鼠肾皮质免疫反应性COX-2的表达是对照动物的2.5 +/- 0.3倍（N = 7）。免疫组化定位显示黄斑致密区及周围皮层厚升肢（cTALH）表达升高。COX-2抑制剂使糖尿病大鼠的COX-2表达降低至对照的1.3 +/- 0.1倍。此外，SC58236降低PAI-1（糖尿病vs治疗组，3.2 +/- 0.5 vs 1.7 +/- 0.2倍对照，N = 7, P < 0.05）、血管内皮生长因子（VEGF; 2.0 +/- 0.2 vs 1.2 +/- 0.2; N = 7, P < 0.05）、纤维连接蛋白（2.4 +/- 0.3 vs 1.3 +/- 0.1; N = 7, P < 0.05）和转化生长因子-P （tgf - β; 2.1 +/- 0.2 vs 1.3 +/- 0.2; N = 7, P < 0.05）的表达。sc58236治疗大鼠6周时蛋白尿减少（149 8 vs 92 +/- 8 mg/24 h; N = 7, P < 0.01）。系膜硬化指数，定义为系膜间隙内细胞外基质的增加，在6周时测定；对照组为0.06 +/- 0.01，糖尿病组为2.7 +/- 0.04，治疗组为0.6 +/- 0.03（与糖尿病组比较，P < 0.0001）。这些结果表明，在糖尿病和高血压的实验模型中，抑制COX-2的表达可以减少肾小球和小管间质损伤的潜在介质，也可以减少肾损伤的生化、功能和结构标志物。
Background. We previously reported that renal cortical cyclooxygenase (COX-2) expression increased following subtotal nephrectomy, and chronic treatment with a selective COX-2 inhibitor, SC58236, reduced proteinuria and retarded the development of glomerulosclerosis. The present studies were designed to examine the effects of COX-2 inhibition in a model of diabetic nephropathy.Methods. Rats were divided into three groups: control, diabetic (streptozotocin-induced diabetic animals with superimposed DOCA/salt hypertension; right nephrectomy and DOCA treatment), and treated (administration of the selective COX-2 inhibitor, SC58236, to a subset of diabetic/DOCA/salt rats). Insulin was administered to maintain blood glucose in the 200 to 300 mg/dL range.Results. Systolic blood pressure in the two diabetic groups was elevated within one week and remained elevated until sacrifice at six weeks (control, 108 +/- 2 mm Hg; diabetic, 158 +/- 4 mm Hg; treated, 156 +/- 7 mm Hg). When measured at six weeks, immunoreactive COX-2 expression in the renal cortex of the diabetic rats was 2.5 +/- 0.3-fold of control animals (N = 7). Immunohistochemical localization indicated increased expression in macula densa and surrounding cortical thick ascending limb of Henle (cTALH). The COX-2 inhibitor decreased COX-2 expression in diabetic rats to 1.3 +/- 0.1-fold control. In addition, SC58236 decreased expression of PAI-1 (diabetic vs. treated, 3.2 +/- 0.5 vs. 1.7 +/- 0.2-fold control, N 7, P < 0.05), vascular endothelial growth factor (VEGF; 2.0 +/- 0.2 vs. 1.2 +/- 0.2; N = 7, P < 0.05), fibronectin (2.4 +/- 0.3 to 1.3 +/- 0.1; N 7, P < 0.05) and transforming growth factor-P (TGF-beta; 2.1 +/- 0.2 vs. 1.3 +/- 0.2; N = 7, P < 0.05). Proteinuria at six weeks was decreased in the SC58236-treated rats (149 8 vs. 92 +/- 8 mg/24 h; N = 7, P < 0.01). The mesangial sclerosis index, defined as increases in extracellular matrix within the mesangial space, was determined at six weeks; the control group had an index of 0.06 +/- 0.01, the diabetic group was 2.7 +/- 0.04 and the treated group was 0.6 +/- 0.03 (P < 0.0001 compared to the diabetic group).Conclusions. These results suggest that in an experimental model of diabetes and hypertension, inhibition of COX-2 expression decreases potential mediators of glomerular and tubulointerstitial injury and also decreases biochemical, functional and structural markers of renal injury.