EFFECT OF CYCLOSPORINE ON PRODUCTION, SECRETION AND METABOLISM OF ENDOTHELIN

我们研究了CsA给药对大鼠1）血浆 ET-1、ET-3和ET-1的表达 肾组织中的转化酶（ECE）; 3）输注的125 I- ET-1，和4）重组中性蛋白酶对125 I-ET-1的降解 内肽酶 大鼠给予CsA 6天后， 不足，例如，GFR下降74%。 尿ET排泄 从检测不到的水平增加到31.7 ± 6.0pg/24 h，而血浆 ET水平无变化。 逆转录后， 定量聚合酶链反应（RT-PCR）显示ET-1-mRNA 肾髓质中ET-3表达增加59%， 而欧洲经委会没有变化。 既不接受CsA急性治疗也不接受CsA慢性治疗 影响125 I-ET-1从血液或肾脏中的清除 和肺对肽的摄取。 此外，CsA不影响 高纯度重组中性粒细胞对125 I-ET-1的降解 内肽酶，一种众所周知的内皮素酶。 提示：1）尿ET水平升高， CsA治疗后发生的肾源性疾病， 增加肾脏合成Et，2）调节ET的产生 ET-1和ET-2在mRNA转录水平的表达 ET-3是独立调节的。

We investigated the effects of CsA administration to rats on 1)plasma and urinary levels of ET, 2) expression of ET-1, ET-3 and endothelin converting enzyme (ECE) in renal tissue, 3)clearance of infused 125 I- ET-1, and 4)degradation of 125I-ET-1 by recombinant neutral endopeptidase. Rats given CsA for 6 days developed severe renal insufficiency, e.g., GFR decreased 74%. Urinary excretion of ET increased from an undetectable level to 31.7+6.0pg/24h, while plasma levels of ET were unchanged. Reverse transcription followed by a quantitative polymerase chain reaction (RT-PCR) revealed that ET-1-mRNA in the renal medulla increased 59%, while the expression of both ET-3 and ECE was unchanged. Neither acute nor chronic treatment with CsA affected either the clearance of 125I-ET-1 from the blood or the renal and pulmonary uptake of the peptide. Moreover, CsA did not affect the degradation of 125I-ET-1 by highly purified recombinant neutral endopeptidase, a well known endothelinase. These findings indicate that: 1) the elevated urinary ET levels occurring afer CsA treatment originate from the kidney, and reflect increased renal synthesis of Et, 2) the production of ET is regulated at the level of mRNA transcription, and 3) the expressions of ET-1 and ET-3 are regulated independently.