Cheng Hui-Fang, Wang Connie J, Moeckel Gilbert W, Zhang Ming-Zhi, McKanna James A, Harris Raymond C
George M. O'Brien Kidney Disease Center and Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2372, USA.
Kidney Int. 2002 Sep;62(3):929-39. doi: 10.1046/j.1523-1755.2002.00520.x.
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.
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.
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-beta (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).
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.
我们之前报道过，肾皮质环氧化酶（COX-2）的表达在肾次全切除术后增加，并且用选择性COX-2抑制剂SC58236进行长期治疗可减少蛋白尿并延缓肾小球硬化的发展。本研究旨在检测COX-2抑制在糖尿病肾病模型中的作用。
将大鼠分为三组：对照组、糖尿病组（链脲佐菌素诱导的糖尿病动物，伴有DOCA/盐性高血压；右肾切除并给予DOCA治疗）和治疗组（对一部分糖尿病/DOCA/盐大鼠给予选择性COX-2抑制剂SC58236）。给予胰岛素以维持血糖在200至300mg/dL范围内。
两个糖尿病组的收缩压在一周内升高，并一直保持升高直至六周时处死（对照组，108±2mmHg；糖尿病组，158±4mmHg；治疗组，156±7mmHg）。在六周时检测，糖尿病大鼠肾皮质中免疫反应性COX-2的表达是对照动物的2.5±0.3倍（N = 7）。免疫组织化学定位显示致密斑和周围髓袢升支粗段（cTALH）中表达增加。COX-2抑制剂使糖尿病大鼠的COX-2表达降至对照的1.3±0.1倍。此外，SC58236降低了纤溶酶原激活物抑制剂-1（PAI-1）的表达（糖尿病组与治疗组相比，分别为对照的3.2±0.5倍与1.7±0.2倍，N = 7，P < 0.05）、血管内皮生长因子（VEGF；2.0±0.2倍与1.2±0.2倍；N = 7，P < 0.05）、纤连蛋白（2.4±0.3倍降至1.3±0.1倍；N = 7，P < 0.05）和转化生长因子-β（TGF-β；2.1±0.2倍与1.3±0.2倍；N = 7，P < 0.05）。SC58236治疗的大鼠在六周时蛋白尿减少（149±8与92±8mg/24h；N = 7，P < 0.01）。系膜硬化指数定义为系膜区内细胞外基质的增加，在六周时测定；对照组指数为0.06±0.01，糖尿病组为2.7±0.04，治疗组为0.6±0.0 (与糖尿病组相比，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表达可减少肾小球和肾小管间质损伤的潜在介质，也可降低肾损伤的生化、功能和结构标志物。
