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


METHODS
The cecum was ligated and punctured in rats under anesthesia. CPU0213 (30 mg .kg(-1).d(-1), bid, sc X 3 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, ET(A), ET(B), iNOS, and tumor necrosis factor-alpha in the renal cortex was significant (P<0.01). The protein amount of activated NF-kappaB was significantly increased (P<0.01) in comparison with the sham operation group. All of these changes were significantly reversed after CPU0213 administration.


CONCLUSIONS
Upregulation of the ET signaling pathway and NF-kappaB play an important role in the ARF of septic shock. Amelioration of renal lesions was achieved by suppressing the ET(A) and ET(B) receptors in the renal cortex following CPU0213 medication.
He
Hai-bo
HB
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Dai
De-zai
DZ
Dai
Yin
Y
D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000097:blood / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000097:blood / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
C513821:CPU0213; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016328:NF-kappa B; D011720:Pyrazoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II