Zoja C, Donadelli R, Corna D, Testa D, Facchinetti D, Maffi R, Luzzana E, Colosio V, Bertani T, Remuzzi G
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Am J Kidney Dis. 1997 Feb;29(2):254-64. doi: 10.1016/s0272-6386(97)90038-x.
In several models of renal disease progression, angiotensin-converting enzyme (ACE) inhibitors reduced proteinuria and limited glomerulosclerosis, which suggested that reduction of renal angiotensin II (Ang II) activity is crucial for the preservation of glomerular structure and function. However, it cannot be ruled out that other hormonal systems, including inhibition of the bradykinin breakdown, also play a role. We compared the effects of chronic treatment with the ACE inhibitor lisinopril with those of a specific Ang II receptor antagonist, L-158,809, on proteinuria and renal injury in passive Heymann nephritis (PHN), a model of immune renal disease that closely resembles human membranous nephropathy, with long-lasting proteinuria followed by tubulointerstitial damage and glomerulosclerosis. Passive Heymann nephritis was induced with 0.5 mL/100 g of rabbit anti-Fx1A antibody in 24 male Sprague-Dawley rats. The animals were divided into three groups of eight rats each, and were given the following in the drinking water on a daily basis: lisinopril (40 mg/L), L-158,809 (50 mg/L), or no therapy. Treatment started at day 7 (proteinuria was already present) and lasted 12 months. Eight normal rats were used as controls. Untreated PHN rats developed hypertension, while rats with PHN given lisinopril or L-158,809 all had systolic blood pressure values even lower than those of normal rats. Urinary protein excretion progressively increased with time in untreated PHN rats, who developed tubulointerstitial damage and glomerulosclerosis. Both lisinopril and L-158,809 exhibited a potent antiproteinuric effect and preserved glomerular and tubular structural integrity at a similar extent. Renal gene expression of transforming growth factor-beta and extracellular matrix proteins was also effectively reduced by the two treatments. These results indicate that ACE inhibitors and Ang II receptor antagonists are equally effective in preventing renal injury in PHN and suggest that the renoprotective effects of ACE inhibitors in this model are solely due to inhibition of Ang II.
在几种肾脏疾病进展模型中，血管紧张素转换酶（ACE）抑制剂可减少蛋白尿并限制肾小球硬化，这表明降低肾脏血管紧张素II（Ang II）活性对于维持肾小球结构和功能至关重要。然而，不能排除其他激素系统，包括抑制缓激肽降解，也发挥作用。我们比较了用ACE抑制剂赖诺普利和特异性Ang II受体拮抗剂L-158,809长期治疗对被动型Heymann肾炎（PHN）蛋白尿和肾损伤的影响，PHN是一种免疫性肾脏疾病模型，与人类膜性肾病非常相似，有持续性蛋白尿，随后出现肾小管间质损伤和肾小球硬化。给24只雄性Sprague-Dawley大鼠注射0.5 mL/100 g兔抗Fx1A抗体诱导被动型Heymann肾炎。将动物分为三组，每组8只大鼠，每天在饮用水中给予以下药物：赖诺普利（40 mg/L）、L-158,809（50 mg/L）或不进行治疗。治疗从第7天开始（此时蛋白尿已经出现），持续12个月。8只正常大鼠用作对照。未经治疗的PHN大鼠出现高血压，而给予赖诺普利或L-158,809的PHN大鼠收缩压值甚至低于正常大鼠。未经治疗的PHN大鼠尿蛋白排泄随时间逐渐增加，出现肾小管间质损伤和肾小球硬化。赖诺普利和L-158,809均表现出强大的抗蛋白尿作用，并在相似程度上维持肾小球和肾小管结构完整性。两种治疗方法还有效降低了转化生长因子-β和细胞外基质蛋白的肾脏基因表达。这些结果表明，ACE抑制剂和Ang II受体拮抗剂在预防PHN肾损伤方面同样有效，并表明ACE抑制剂在该模型中的肾脏保护作用完全归因于对Ang II的抑制。
