Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Am J Physiol Heart Circ Physiol. 2011 Jun;300(6):H2316-22. doi: 10.1152/ajpheart.01259.2010. Epub 2011 Mar 25.
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.
在糖尿病中诱导肾环氧化酶-2（COX-2）的产生与高血压或单侧肾切除叠加的模型中的肾功能和结构变化有关。我们检查了 3 个月的用高度选择性 COX-2 抑制剂（SC-58236）治疗链脲佐菌素糖尿病大鼠的保护作用，就白蛋白尿、肾肥大以及 TNF-α和 TGF-β的排泄而言，这些因素也与糖尿病的有害肾脏作用有关。SC-58236（3mg·kg(-1)·day(-1)）治疗糖尿病大鼠可减少 PGE(2)、6-酮-PGF(1α)和血栓烷 B(2)的尿排泄，所有这些在糖尿病大鼠中均高于同龄非糖尿病大鼠。然而，血清血栓烷 B(2)水平不变，证实了 SC-58236对 COX-2 的选择性。COX-2 抑制剂治疗糖尿病大鼠的肾保护作用体现在明显减少白蛋白尿、降低肾脏重量与体重比以及 TGF-β排泄，并明显减少 TNF-α的尿排泄。SC-58236 的保护作用独立于血浆葡萄糖水平或血清晚期糖基化终产物水平的变化，这些与未治疗的糖尿病大鼠没有区别。在另一项研究中，在糖尿病大鼠中用 SC-58236 抑制 COX-2 4 周，肌酐清除率与对照大鼠没有区别。这些结果证实了在链脲佐菌素糖尿病大鼠中抑制 COX-2 可提供肾脏保护，并表明 COX-2 的诱导先于细胞因子、TNF-α和 TGF-β的增加。
