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Published on: July 3, 2013
A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats
J L Wang1, H F Cheng, S Shappell
1George 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.
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.
Insights
Selective cyclooxygenase-2 (COX-2) inhibition in rats with chronic kidney disease reduced proteinuria and kidney damage. COX-2 inhibitors may be beneficial for progressive renal injury, potentially in combination with ACE inhibitors.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Cyclooxygenase-2 (COX-2) expression increases in specific kidney cells after subtotal renal ablation in rats.
- This elevated COX-2 is observed in the macula densa/cortical thick ascending limb and glomerular podocytes.
Purpose of the Study:
- To investigate the functional impact of increased COX-2 expression following kidney injury.
- To evaluate the renoprotective effects of a selective COX-2 inhibitor (SC58236) and an angiotensin-converting enzyme inhibitor (enalapril) in a rat model of chronic kidney disease.
Main Methods:
- Rats underwent subtotal renal ablation and were treated with SC58236, vehicle, enalapril, or enalapril + SC58236 for 6-10 weeks.
- Blood pressure, proteinuria, glomerular sclerosis, and gene expression (TGF-β1, collagen III, collagen IV) were assessed.
Main Results:
- SC58236 alone did not significantly affect hypertension but reduced proteinuria to levels comparable with enalapril.
- SC58236 treatment significantly decreased glomerular sclerosis and partially inhibited increases in TGF-β1 and collagen mRNA expression.
- Combined enalapril and SC58236 treatment also showed benefits in reducing blood pressure and proteinuria.
Conclusions:
- Chronic administration of a selective COX-2 inhibitor can attenuate the progression of experimental renal injury.
- COX-2 inhibitors show potential as a therapeutic strategy for chronic kidney disease, possibly in conjunction with angiotensin-converting enzyme inhibitors.
- Further research is needed to elucidate the precise mechanisms underlying COX-2 inhibition-mediated renoprotection.
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