Feldman D L, Mogelesky T C, Chou M, Jeng A Y
Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S342-5. doi: 10.1097/00005344-200036051-00099.
Endothelin-1 (ET-1) has been implicated in the pathogenesis of various renal diseases. The purpose of this study was to investigate the effect of CGS 26303, an endothelin-converting enzyme (ECE) inhibitor, on puromycin aminonucleoside (PA)-induced nephrosis in rats. The animals (three groups; n = 8 per group) received 50 mg/kg PA or NaCl, intravenously. CGS 26303 (5 mg/kg/day, s.c. via osmotic minipumps) or vehicle was administered to the PA-treated animals for 4 weeks, starting within 5 min after PA injection. Uninephrectomy was performed 2 weeks after PA to accelerate the renal damage. Rats received no treatment between 4 and 8 weeks. At 8 weeks rats were euthanized and kidneys removed for histology and analysis for mRNA levels of endothelin-A- and -B- (ET(A) and ET(B)) receptors and ECE-1. Glomeruli (100 glomeruli/section; 800/group) were graded as normal (N), mild lesion (ML = few periodic acid-Schiff positive [PAS+] droplets and small adhesions to Bowman's capsule), and moderate to severe lesion (SL = many PAS+ droplets, adhesions to and thickening of Bowman's capsule, mesangial expansion, and cystic dilations of glomerular capillaries). In the PA + vehicle group N, ML and SL were 39.5%, 11.9% and 48.6%, respectively, while the respective values were 68.3%, 9.4%, and 22.3% in PA + CGS 26303-treated rats. However, the renal mRNA levels of ECE-1 and ET(A)- and ET(B)-receptors were not significantly different among the three groups. These results confirm the efficacy of ECE inhibition in this disease model. On the other hand, the mRNA data suggest that either there was no change in the expression of the genes examined or their levels had already returned to normal by the end of the experiment.
内皮素 -1（ET -1）与多种肾脏疾病的发病机制有关。本研究的目的是探讨内皮素转换酶（ECE）抑制剂CGS 26303对嘌呤霉素氨基核苷（PA）诱导的大鼠肾病的影响。动物（三组，每组n = 8）静脉注射50 mg/kg PA或NaCl。PA处理的动物在PA注射后5分钟内开始，通过渗透微型泵皮下给予CGS 26303（5 mg/kg/天）或赋形剂，持续4周。PA注射2周后进行单侧肾切除术以加速肾脏损伤。大鼠在4至8周期间未接受治疗。8周时处死大鼠，取出肾脏进行组织学检查，并分析内皮素A和B（ET(A)和ET(B)）受体以及ECE -1的mRNA水平。肾小球（每切片100个肾小球；每组800个）分为正常（N）、轻度病变（ML = 少量过碘酸希夫阳性[PAS +]液滴和与鲍曼囊的小粘连）和中度至重度病变（SL = 许多PAS +液滴、与鲍曼囊的粘连和增厚、系膜扩张以及肾小球毛细血管的囊性扩张）。在PA +赋形剂组中，N、ML和SL分别为39.5%、11.9%和48.6%，而在PA + CGS 26303处理的大鼠中，相应的值分别为68.3%、9.4%和22.3%。然而，三组之间ECE -1以及ET(A)和ET(B)受体的肾脏mRNA水平没有显著差异。这些结果证实了ECE抑制在该疾病模型中的有效性。另一方面，mRNA数据表明，所检测基因的表达要么没有变化，要么在实验结束时其水平已经恢复正常。
