sc-236 and Proteinuria

To investigate the effects of cyclooxygenase-2 (COX-2) inhibition on renal injury of mice, ROP mice were subjected to subtotal ablation ('remnant'). A subset of the remnant group was treated with a selective COX-2 inhibitor, SC58236, in the drinking water. At 12 weeks the remnant group developed significant albuminuria (181.3 +/- 15.8 microg/24 h), which was blunted by SC58236 treatment (138.9 +/- 17.1; p < 0.05 compared to remnant). SC58236 did not alter systemic blood pressure or GFR significantly. Immunoreactive COX-2 was upregulated in remnant (1.88 +/- 0.35 fold sham, n = 8, p < 0.05), which was blunted by SC58236 (to 1.26 +/- 0.31 fold sham). Collagen IV mRNA increased significantly in remnant kidneys (2.69 +/- 0.34 fold sham, n = 8, p < 0.05), and this increase was inhibited by SC58236 treatment (to 1.84 +/- 0.32 fold control). Immunoreactive TGF-beta1, connective tissue growth factor, HGF receptor, c-Met, and fibronectin all increased in remnant (2.85 +/- 0.51, 3.83 +/- 0.55, 2.56 +/- 0.31, and 2.80 +/- 0.39 fold sham respectively, n = 4-8, p < 0.05), and SC58236 blunted the increases (to 1.45 +/- 0.34, 1.85 +/- 0.13, 1.75 +/- 0.30, and 1.60 +/- 0.32 fold sham). Immunohistochemistry indicated that the major localization for these progression factors was in the tubulointerstitium, especially in the scar area, which is in agreement with the expression of a macrophage marker, F4/80. Therefore, these results indicate that in a mouse model of subtotal renal ablation, COX-2 inhibition blocks expression of mediators of renal tubulointerstitial injury.

Topics: Animals; Connective Tissue Growth Factor; Cyclooxygenase 2 Inhibitors; Fibronectins; Glomerulosclerosis, Focal Segmental; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Tubules; Mice; Mice, Inbred Strains; Nephrectomy; Proteinuria; Proto-Oncogene Proteins c-met; Pyrazoles; Sulfonamides; Tissue Distribution

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.. To evaluate the functional consequences of this increased COX-2 expression, male rats were subjected to subtotal renal ablation and divided into four groups: (1) 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.. 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-beta1 mRNA expression and increases in collagen III and collagen IV mRNA expression.. 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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Combinations; Enalapril; Hypertension; Isoenzymes; Kidney; Kidney Glomerulus; Male; Nephrectomy; Prostaglandin-Endoperoxide Synthases; Proteinuria; Pyrazoles; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sclerosis; Sulfonamides