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.

Fig. 1.

Effect of treatment of diabetic rats with SC-58236 (SC; 3 mg·kg⁻¹·day⁻¹) for 12 wk on serum levels of N^ε-(carboxymethyl) lysine (CML) where n = 8 for the untreated diabetic group, n = 3 for the treated diabetic group, and n = 5 for the control group. STZ, streptozotocin. *P < 0.05 vs. the control group (CON).

Fig. 2.

Urinary excretion (in ng/h) of 6-ketoPGF_1α (**P < 0.01 vs. other groups), PGE₂ (*P < 0.05 vs. CON; **P < 0.01 vs. STZ), and thromboxane B₂ (TxB₂; **P < 0.01 vs. other groups) in untreated diabetic rats (STZ; n = 7), diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹; STZ + SC; n = 4) for 3 mo, and age-matched control rats (CON; n = 5).

Fig. 3.

A: increases in perfusion pressure (PP; in mmHg) in response to arachidonic acid (AA) in isolated perfused kidneys from age-matched control rats (CON; n = 4), diabetic rats (STZ; n = 5), and diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 12 wk (STZ + SC; n = 4). *P < 0.05 vs. control; **P < 0.01 vs. control. B: release of 6-ketoPGF_1α (in pg/min) from isolated perfused kidneys of age-matched control rats (CON; n = 4), untreated diabetic rats (STZ; n = 5), and diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 12 wk (STZ + SC; n = 4).

Fig. 4.

A: urinary excretion of TNF-α (in pg/8 h) in age-matched control rats (CON; n = 5), untreated diabetic rats (STZ; n = 6), and diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 12 wk (STZ + SC; n = 5). **P < 0.01 vs. citrate and STZ + SC. B: urinary excretion of albumin (UAlb; in μg/8 h) in age-matched control rats (CON; n = 4), untreated diabetic rats (STZ; n = 6), and diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 12 wk (STZ + SC; n = 5). *P < 0.05 vs. CON and STZ + SC.

Fig. 5.

A: urinary excretion of TGF-β (in pg/8 h) in age-matched control rats (CON; n = 5), untreated diabetic rats (STZ; n = 6), and diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 12 wk (STZ + SC; n = 4). *P < 0.01 vs. control. B: left kidney weight-to-body weight ratio in untreated diabetic rats (STZ; n = 5), diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 12 wk (STZ + SC; n = 3), and nondiabetic rats (CON; n = 5). *P < 0.05 vs. STZ; **P < 0.01 vs. STZ and STZ + SC.

Fig. 6.

Creatinine clearance (Cl_Cr; ml/min) in untreated diabetic rats (STZ; n = 4), diabetic rats treated with SC-58236 (3 mg·kg⁻¹·day⁻¹) for 4 wk (STZ + SC; n = 5), and age-matched control rats (CON; n = 6). P = 0.053 STZ vs. CON.