Largo R, Gómez-Garre D, Liu X H, Alonso J, Blanco J, Plaza J J, Egido J
Renal Research Laboratory Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Hypertension. 1997 May;29(5):1178-85. doi: 10.1161/01.hyp.29.5.1178.
Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription-polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.
内皮素（ET-1）是一种强效血管收缩剂，在肾循环和肾小管功能的调控中发挥重要作用。该肽在系统性高血压和肾衰竭发病机制中的作用仍 largely 未明确。在 20 周龄时进行单侧肾切除的自发性高血压大鼠（SHR）（UNX-SHR）并随访至 45 周龄，我们通过逆转录 - 聚合酶链反应测定肾组织中 ET-1 基因表达，并通过原位杂交在石蜡包埋的肾切片中确定其定位。选择年龄匹配的 SHR 和血压正常的 Wistar-Kyoto（WKY）大鼠作为对照。随访结束时，UNX-SHR 出现高收缩压、严重蛋白尿、系膜扩张、局灶性和节段性肾小球硬化以及肾小管间质病变。与 WKY 和 SHR 相比，UNX-SHR 在肾皮质和髓质中 ET-1 基因表达增加。通过原位杂交和免疫过氧化物酶染色，在系膜和肾小球上皮细胞以及一些近端小管和血管中可见 ET-1 基因和蛋白的过表达。肾刷状缘中的血管紧张素转换酶（ACE）活性显著增加。由于在系膜细胞中，血管紧张素 II 诱导 ET-1 合成，一组 UNX-SHR 从单侧肾切除时开始接受 ACE 抑制剂喹那普利。这些动物的血压、蛋白尿、血清和刷状缘 ACE 活性以及所有肾区中 ET-1 的表达和合成均降低。总体而言，这些数据表明，与 SHR 和 WKY 大鼠相比，UNX-SHR 在肾脏的几个结构中 ET-1 基因和蛋白上调。喹那普利降低了 ACE 活性以及 ET-1 的表达和合成，同时蛋白尿和形态学病变有所改善。ACE 抑制剂的有益作用可能归因于血管紧张素 II 和 ET-1 生成的减少。
