title: Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats.
abstract: The induction of renal cyclooxygenase-2 (COX-2) in diabetes has been implicated in the renal functional and structural changes in models where hypertension or uninephrectomy was superimposed. We examined the protective effects of 3 mo treatment of streptozotocin-diabetic rats with a highly selective COX-2 inhibitor (SC-58236) in terms of albuminuria, renal hypertrophy, and the excretion of TNF-α and TGF-β, which have also been implicated in the detrimental renal effects of diabetes. SC-58236 treatment (3 mg·kg(-1)·day(-1)) of diabetic rats resulted in reduced urinary excretion of PGE(2), 6-ketoPGF(1α), and thromboxane B(2), all of which were increased in the diabetic rat compared with age-matched nondiabetic rats. However, serum thromboxane B(2) levels were unchanged, confirming the selectivity of SC-58236 for COX-2. The renal protective effects of treatment of diabetic rats with the COX-2 inhibitor were reflected by a marked reduction in albuminuria, a reduction in kidney weight-to-body weight ratio, and TGF-β excretion and a marked decrease in the urinary excretion of TNF-α. The protective effects of SC-58236 were independent of changes in plasma glucose levels or serum advanced glycation end-product levels, which were not different from those of untreated diabetic rats. In an additional study, the inhibition of COX-2 with SC-58236 for 4 wk in diabetic rats resulted in creatinine clearance rates not different from those of control rats. These results confirm that the inhibition of COX-2 in the streptozotocin-diabetic rat confers renal protection and suggest that the induction of COX-2 precedes the increases in cytokines, TNF-α, and TGF-β.
authors: Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. john_quilley@nymc.edu
authors: J
authors: J
authors: Quilley
authors: M
authors: M
authors: Santos
authors: P
authors: P
authors: Pedraza
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000517:prevention & control* / Q000652:urine; D004195:Disease Models, Animal; D008297:Male; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000009:adverse effects; D013449:Sulfonamides / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000652:urine; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000652:urine; D000096926:Benzenesulfonamides
chemical_list: D001786:Blood Glucose; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013311:Streptozocin; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides