Rofecoxib decreases renal injury in obese Zucker rats

Clinical Science - Tập 107 Số 6 - Trang 561-570 - 2004
Aparajita Dey1, Christine Maric2, Wayne Kaesemeyer3, Constantine Z. Zaharis1, J. Philip Stewart1, Jennifer S. Pollock3,1, John D. Imig4,1
1Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, U.S.A.
2Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, Washington, DC 20007, U.S.A.
3Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
4Department of Physiology, Medical College of Georgia, Augusta, GA 30912, U.S.A.

Tóm tắt

The present study tested the hypothesis that altered vascular regulation of arachidonic acid enzymes in obese Zucker rats contributes to renal damage. Protein expression of CYP450 (cytochrome P450) and COX (cyclo-oxygenase) enzymes in renal microvessels was studied in obese and lean Zucker rats at 20–21 weeks of age. Body weight and blood glucose averaged 649±13 g and 142±10 mg/dl in obese Zucker rats compared with 437±10 g and 111±5 mg/dl in age-matched lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased and CYP2C protein levels decreased in obese Zucker rats. TX (thromboxane) B2 excretion was 2-fold higher and PG (prostaglandin) E2 excretion significantly lower in obese Zucker rats. Additional studies investigated the ability of the COX-2 inhibitor, rofecoxib, to slow the progression of renal injury in obese Zucker rats. Rofecoxib treatment decreased urinary PGF2α and 8-isoprostane levels in obese Zucker rats. Renal microvessel mRNA expression of pro-inflammatory chemokines was decreased in COX-2-inhibitor-treated obese Zucker rats. Urinary albumin excretion, an index of kidney damage, averaged 95±11 mg/day in vehicle-treated and 9±1 mg/day in rofecoxib-treated obese Zucker rats. Glomerulosclerosis, characterized by mesangial expansion, tubulo-interstitial fibrosis and extracellular matrix accumulation, was prominent in obese Zucker rats compared with a lack of damage in age-matched lean Zucker rats and rofecoxib-treated obese Zucker rats. These results suggest that altered vascular arachidonic acid enzymes contribute to the renal damage, and that COX-2 inhibition decreases glomerular injury in obese Zucker rats.

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Clinical Science

Tập 107 Số 6

561-570

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