Prevention of acute renal failure by anti-endothelin converting enzyme.

内皮素-1在环孢菌素A诱导的急性肾功能衰竭中起重要作用。内皮素转换酶-1（ECE-1）是产生内皮素的关键酶。为探讨ECE-1在环孢菌素A（CsA）诱导的肾小球和肾小管功能障碍中的作用，本研究观察了CsA对肾小球和肾小管mENA及ECE-1、ET-1前体、ETA和ETB型受体蛋白表达的影响。在肾小球30 ~ 60 mm处，ET-1前体迅速升高，血浆ET-1水平随之升高。结果表明，在环孢素A诱导的急性肾功能衰竭中，肾小球和肾小管ECE-1表达下调可能是ET系统的防御机制之一，这种下调可能是由ET-1升高或环孢素A本身引起的。为了研究内皮素-1（ET-1）下调内皮素-1（ECE-1）mRNA表达的确切机制，我们在培养的内皮细胞中研究了ET-1的作用。ETA孵育6小时后，ECE-1 mRNA表达显著下降。这种作用可通过与特异性ETB受体拮抗剂BQ 788共孵育而消除，但不能通过与特异性ETA受体拮抗剂BQ 123共孵育而消除。提示ET-1通过ETB受体抑制内皮细胞ECE-1的表达，提示ET-1对内皮细胞ECE-1的作用存在反馈机制。

Endothelin-1 is thought to play a significant role in acute renal failure induced by cyclosporin A.Endothelin converting enzyme-1 (ECE-1) is a key enzyme to produce endothelin. To investigate the role of ECE-1 in the glomerular and tubular dysfunction induced by cyclosporin A, the effects of cyclosporin A on mENA and protein expression of ECE-1, prepro-ET-1, and ETA and ETB type receptor were studied. Prepro-ET-1 rapidly increased in glomeruli 30 to 60 mm. This rapid increase was followed byan increase in plasma ET-1 levels. These increases were followed by decreased expression of ECE- 1, ETA and ETB type receptor mRNA It is suggested that downregulation of glomerular and tubular ECE-1 expression may be one of defense mechanisms of ET system in acute renal failure induced by cyclosporin A.This downregulation may be caused by increased ET-1 or cyclosporin A itself. To investigate the precise mechanism of downregulation of ECE-1 mRNA, the effects of ET-1 was studied in cultured endothelial cells. Incubation of ETA for 6 hours caused a significant decrease in ECE-1 mRNA expression. This effect was was abolished by co-incubation with BQ788, a specific ETB receptor antagonist , but not by co-incubation with BQ123, a specific ETA receptor antagonist. These results suggested that ET-1 suppressed ECE-1 expression through ETB receptor, indicating the existence of a feedback mechanism of FT-1 on ECE-1 in endothelial cells.