A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats.
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: (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.


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-beta1 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.
Wang
J L
JL
George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology, Departments of Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cheng
H F
HF
Shappell
S
S
Harris
R C
RC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004338:Drug Combinations; D004656:Enalapril / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology; D007527:Isoenzymes / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D009392:Nephrectomy / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D011507:Proteinuria / Q000652:urine*; D011720:Pyrazoles; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D012598:Sclerosis; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D000806:Angiotensin-Converting Enzyme Inhibitors; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D004656:Enalapril; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D012333:RNA, Messenger; D012083:Renin; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides