CPU0213,a novel endothelin receptor antagonist,ameliorates septic renal lesion by suppressing ET system and NF-κB in rats  

作　　者：Hai-bo HE De-zai DAI Yin DAI 

机构地区：[1]Research Division of Pharmacology, China Pharmaceutical University Nanjing 210009, China

出　　处：《Acta Pharmacologica Sinica》2006年第9期1213-1221,共9页中国药理学报（英文版）

基　　金：Project supported by the National Natural Science Foundation of China(№30230170 and №30572193).

摘　　要：Aim： To examine whether a novel endothelin receptor antagonist, CPU0213, is effective in relieving the acute renal failure （ARF） of septic shock by suppressing the activated endothelin-reactive oxygen species （ET-ROS） pathway and nuclear factor kappa B （NF-κB）. Methods： The cecum was ligated and punctured in rats under anesthesia. CPU0213 （30 mg·kg^-1·d^-1, bid, scx3 d） was administered 8 h after surgical operation. Results： In the untreated septic shock group, the mean arterial pressure and survival rate were markedly decreased （P〈0.01）, and heart rate, weight index of kidney, serum creatinine and blood urea nitrogen, 24 h urinary protein and creatinine were significantly increased （P〈0.01）. The levels of ET-1, total NO synthetase （tNOS）, indusible nitric oxide synthetase （iNOS）, nitric oxide （NO）, and ROS in serum and the renal cortex were markedly increased （P〈 0.01）. The upregulation of the mRNA levels of preproET-1, endothelin converting enzyme, ETA, ETB, iNOS, and tumor necrosis factor-alpha in the renal cortex was significant （P〈0.01）. The protein amount of activated NF-κB was significantly increased （P〈0.01） in comparison with the sham operation group. All of these changes were significantly reversed after CPU0213 administration. Conclusion： Upregulation of the ET signaling pathway and NF-κB play an important role in the ARF of septic shock. Amelioration of renal lesions was achieved by suppressing the ETA and ETB receptors in the renal cortex following CPU0213 medication.Aim： To examine whether a novel endothelin receptor antagonist, CPU0213, is effective in relieving the acute renal failure （ARF） of septic shock by suppressing the activated endothelin-reactive oxygen species （ET-ROS） pathway and nuclear factor kappa B （NF-κB）. Methods： The cecum was ligated and punctured in rats under anesthesia. CPU0213 （30 mg·kg^-1·d^-1, bid, scx3 d） was administered 8 h after surgical operation. Results： In the untreated septic shock group, the mean arterial pressure and survival rate were markedly decreased （P〈0.01）, and heart rate, weight index of kidney, serum creatinine and blood urea nitrogen, 24 h urinary protein and creatinine were significantly increased （P〈0.01）. The levels of ET-1, total NO synthetase （tNOS）, indusible nitric oxide synthetase （iNOS）, nitric oxide （NO）, and ROS in serum and the renal cortex were markedly increased （P〈 0.01）. The upregulation of the mRNA levels of preproET-1, endothelin converting enzyme, ETA, ETB, iNOS, and tumor necrosis factor-alpha in the renal cortex was significant （P〈0.01）. The protein amount of activated NF-κB was significantly increased （P〈0.01） in comparison with the sham operation group. All of these changes were significantly reversed after CPU0213 administration. Conclusion： Upregulation of the ET signaling pathway and NF-κB play an important role in the ARF of septic shock. Amelioration of renal lesions was achieved by suppressing the ETA and ETB receptors in the renal cortex following CPU0213 medication.

关 键 词：septic shock acute renal failure endothelin receptor antagonist NF-ΚB reactive oxygen species 

分 类 号：R692[医药卫生—泌尿科学]