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Published on: October 26, 2020
Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney
Clarice Kazue Fujihara1, Gláucia Rutigliano Antunes, Ana Lúcia Mattar
1Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Background:
The pathogenesis of progressive nephropathies involves hemodynamic and inflammatory factors. In the 5/6 nephrectomy model, a selective increase of cyclooxygenase-2 (COX-2) expression was shown, whereas treatment with a nonsteroidal anti-inflammatory or a specific COX-2 inhibitor was renoprotective. We investigated in the 5/6 nephrectomy model (1) the renal distribution of COX-2; (2) the hemodynamic and cellular mechanisms by which chronic COX-2 inhibition prevents renal injury.
Methods:
After 5/6 nephrectomy, adult male Munich-Wistar rats were subdivided in two groups: 5/6 nephrectomy (N=20), receiving vehicle, and 5/6 nephrectomy + celecoxib (N=19), treated orally with the COX-2 inhibitor, celecoxib, 10 mg/kg/day. Untreated and treated (celecoxib) sham-operated rats were also studied. Renal hemodynamics were examined at 4 weeks, whereas renal morphologic/immunohistochemical studies were carried at 8 weeks.
Results:
At 4 weeks, 5/6 nephrectomy rats exhibited marked systemic and glomerular hypertension. Celecoxib attenuated both systemic and glomerular hypertension, without affecting glomerular filtration rate (GFR). At 8 weeks, glomerulosclerosis and interstitial expansion were evident in 5/6 nephrectomy rats, and markedly attenuated in 5/6 nephrectomy rats given celecoxib. In both sham-operated and 5/6 nephrectomy rats, COX-2 was expressed at the macula densa. The extent of COX-2 expression at the macula densa was nearly tripled by celecoxib, indicating the existence of a feedback mechanism. In 5/6 nephrectomy rats, COX-2 was also expressed in glomeruli, arterioles, and the cortical interstitium, mostly at inflamed or sclerosing areas. Celecoxib markedly attenuated renal injury, inflammation, and ectopic COX-2 expression in 5/6 nephrectomy rats.
Conclusion:
Chronic COX-2 inhibition attenuated progressive nephropathy by reducing glomerular hypertension, renal inflammation, and ectopic COX-2 expression, indicating a complex contribution of COX-2 to progressive renal injury in 5/6 nephrectomy rats.
Insights
Chronic cyclooxygenase-2 (COX-2) inhibition reduced kidney damage in a rat model of progressive nephropathy. Celecoxib treatment attenuated hypertension and inflammation, highlighting COX-2
Area of Science:
- Nephrology
- Pharmacology
- Renal Pathophysiology
Background:
- Progressive nephropathies involve hemodynamic and inflammatory pathways.
- Cyclooxygenase-2 (COX-2) expression increases in the 5/6 nephrectomy model.
- NSAIDs and COX-2 inhibitors show renoprotective effects.
Purpose of the Study:
- Investigate renal cyclooxygenase-2 (COX-2) distribution in 5/6 nephrectomy rats.
- Elucidate hemodynamic and cellular mechanisms of COX-2 inhibition in preventing renal injury.
Main Methods:
- Adult male Munich-Wistar rats underwent 5/6 nephrectomy or sham operation.
- Groups received either vehicle or celecoxib (10 mg/kg/day) orally.
- Renal hemodynamics assessed at 4 weeks; morphology and immunohistochemistry at 8 weeks.
Main Results:
- Celecoxib attenuated systemic and glomerular hypertension in nephrectomized rats.
- Glomerulosclerosis and interstitial expansion were reduced by celecoxib.
- COX-2 expression was observed in macula densa, glomeruli, arterioles, and interstitium, with celecoxib reducing ectopic expression.
Conclusions:
- Chronic COX-2 inhibition mitigated progressive nephropathy in rats.
- Reduced glomerular hypertension and renal inflammation were key effects.
- COX-2 plays a complex role in progressive renal injury after 5/6 nephrectomy.
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