Ruiz-Ortega M, Gómez-Garre D, Liu X H, Blanco J, Largo R, Egido J
Renal Unit, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
J Am Soc Nephrol. 1997 May;8(5):756-68. doi: 10.1681/ASN.V85756.
Angiotensin-converting enzyme (ACE) inhibitors diminish proteinuria and the progression to renal failure in several experimental models of renal injury. Endothelin-1 (ET-1) possesses potent biological actions on renal vessels and has been considered as a potential mediator of renal damage. Because angiotensin II (Ang II) induces ET-1 synthesis in endothelial and mesangial cells, we hypothesized that some of the beneficial effects of the ACE inhibitors could result from the blockade of ET-1 synthesis. In a normotensive model of immune-complex nephritis, in which there exists an increase in renal ACE activity, the effect of the ACE inhibitor quinapril on preproET-1 and ETA receptor mRNA expression, as well as on ET-1 protein levels, was examined in this study. In relation to controls, nephritic rats showed an increase in preproET-1 and ETA receptor gene expression in renal cortex and medulla, coinciding with the maximal renal ACE activity. PreproET-1 mRNA (in situ hybridization) and ET-1 protein (immunohistochemistry) were localized in glomerular capillary walls, mesangial and glomerular epithelial cells, as well as in the brush border of some proximal tubules, and in small vessels. In nephritic rats, there was an increase in preproET-1 mRNA levels and ET-1 protein in all of these areas, without modification of their distribution. The administration of the ACE inhibitor quinapril decreased proteinuria and morphological lesions, preproET-1 gene transcription, and ET-1 protein levels, as well as the ETA receptor mRNA. The results from this study show that in a normotensive model of immune-complex nephritis, there was an overexpression of ET-1 in several structures of the kidney that was downregulated by quinapril administration. The beneficial effect of ACE inhibitors could be a result of the modulation of local production of Ang II and ET-1.
在几种肾损伤实验模型中，血管紧张素转换酶（ACE）抑制剂可减少蛋白尿并延缓肾衰竭进展。内皮素-1（ET-1）对肾血管具有强大的生物学作用，被认为是肾损伤的潜在介质。由于血管紧张素II（Ang II）可诱导内皮细胞和系膜细胞合成ET-1，我们推测ACE抑制剂的一些有益作用可能源于对ET-1合成的阻断。在免疫复合物性肾炎的正常血压模型中，肾ACE活性升高，本研究检测了ACE抑制剂喹那普利对前体ET-1和ETA受体mRNA表达以及ET-1蛋白水平的影响。与对照组相比，肾炎大鼠肾皮质和髓质中前体ET-1和ETA受体基因表达增加，与肾ACE活性最高时一致。前体ET-1 mRNA（原位杂交）和ET-1蛋白（免疫组织化学）定位于肾小球毛细血管壁、系膜和肾小球上皮细胞，以及一些近端小管的刷状缘和小血管。在肾炎大鼠中，所有这些区域的前体ET-1 mRNA水平和ET-1蛋白均增加，但其分布未改变。给予ACE抑制剂喹那普利可降低蛋白尿和形态学损伤、前体ET-1基因转录、ET-1蛋白水平以及ETA受体mRNA。本研究结果表明，在免疫复合物性肾炎的正常血压模型中，肾脏多个结构中ET-1过度表达，喹那普利给药可使其下调。ACE抑制剂的有益作用可能是对局部Ang II和ET-1产生进行调节的结果。
