Zoja C, Corna D, Bruzzi I, Foglieni C, Bertani T, Remuzzi G, Benigni A
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Exp Nephrol. 1996 Jul-Aug;4(4):213-21.
In nonimmunological models of renal damage, abnormal traffic of proteins through the glomerular capillary is one of the possible causes of renal disease progression. Here we investigated whether in a model of immune-mediated glomerulonephritis long-lasting proteinuria resulted in renal structural damage and whether chronic treatment with perindopril, an angiotensin-converting enzyme (ACE) inhibitor, lowered proteinuria and retarded disease progression. Passive Heymann nephritis (PHN), a model of human membranous nephropathy, was induced with 0.5 ml/100 g of rabbit anti-Fx1 A antibody in 26 male Sprague-Dawley rats. Animals were then divided into two groups of 13 rats each, given daily vehicle or perindopril (1 mg/kg p.o). Treatment started at day 7 when proteinuria was already present and lasted 12 months. An additional group of normal rats was used as control. Renal biopsies were taken at months 8 and 12. Untreated PHN rats showed a significant increase in systolic blood pressure starting from month 8, that was normalized by perindopril administration. Urinary protein excretion progressively increased with time in untreated PHN rats that developed focal and segmental glomerulosclerosis and tubulointerstitial damage. Perindopril significantly reduced proteinuria and limited glomerular and tubulointerstitial injury. Urinary excretion of endothelin-1 (ET-1) and transforming growth factor-beta 1 (TGF-beta 1), two major mediators of renal damage in other models of glomerulonephritis, increased with time in PHN but only the former correlated with the degree of glomerulosclerosis. The effect of perindopril on proteinuria and renal structural damage was associated with a significant reduction in urinary ET-1 but not TGF-beta 1, suggesting that ET-1 may be an important determinant of disease progression in experimental membranous nephropathy.
在肾损伤的非免疫模型中，蛋白质通过肾小球毛细血管的异常转运是肾病进展的可能原因之一。在此，我们研究了在免疫介导的肾小球肾炎模型中，长期蛋白尿是否会导致肾脏结构损伤，以及血管紧张素转换酶（ACE）抑制剂培哚普利的长期治疗是否能降低蛋白尿并延缓疾病进展。用0.5 ml/100 g兔抗Fx1 A抗体在26只雄性Sprague-Dawley大鼠中诱导出被动性Heymann肾炎（PHN），这是一种人类膜性肾病模型。然后将动物分为两组，每组13只大鼠，分别每日给予赋形剂或培哚普利（口服1 mg/kg）。治疗在第7天开始，此时蛋白尿已经出现，持续12个月。另外一组正常大鼠用作对照。在第8个月和第12个月时进行肾脏活检。未经治疗的PHN大鼠从第8个月开始收缩压显著升高，培哚普利治疗可使其恢复正常。未经治疗且发生局灶节段性肾小球硬化和肾小管间质损伤的PHN大鼠，其尿蛋白排泄随时间逐渐增加。培哚普利显著降低了蛋白尿，并限制了肾小球和肾小管间质损伤。在其他肾小球肾炎模型中，肾损伤的两个主要介质内皮素-1（ET-1）和转化生长因子-β1（TGF-β1）的尿排泄量在PHN中随时间增加，但只有前者与肾小球硬化程度相关。培哚普利对蛋白尿和肾脏结构损伤的作用与尿ET-1的显著降低有关，但与TGF-β1无关，这表明ET-1可能是实验性膜性肾病疾病进展的重要决定因素。
