Zoja Carla, Corna Daniela, Rottoli Daniela, Cattaneo Dario, Zanchi Cristina, Tomasoni Susanna, Abbate Mauro, Remuzzi Giuseppe
Mario Negri Institute for Pharmacological Research, and Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy.
Kidney Int. 2002 May;61(5):1635-45. doi: 10.1046/j.1523-1755.2002.00332.x.
Angiotensin-converting enzyme (ACE) inhibitor therapy given soon after disease induction uniformly prevents proteinuria in virtually all models of disease progression. This does not necessarily apply to patients with proteinuric nephropathies, who might be referred late in the course of their disease. Here we used a severe rat model of passive Heymann nephritis (PHN), which may mimic advanced phases of human membranous nephropathy, to study the response to ACE inhibitor alone or in combination with a HMG CoA reductase inhibitor (statin) that independently of the cholesterol-lowering effect influences pathways involved in inflammatory and fibrogenic processes. Therapies started when animals had massive proteinuria and renal lesions.
PHN was accelerated by uninephrectomy seven days after IV injection of rabbit anti-FX1A antibody. Four months later, when massive proteinuria and renal lesions were present, the rats were divided into five groups and daily given orally: vehicle; lisinopril 40 mg/L; lisinopril 400 mg/L; simvastatin 2 mg/kg b.i.d; or lisinopril 40 mg/L plus simvastatin. Six normal rats served as controls. Animals were sacrificed at 10 months.
By the end of the study three PHN rats died in the vehicle group, four in the group given lisinopril at 40 mg/L and two in the group at 400 mg/L, whereas all rats on simvastatin or combined therapy were alive. Blood pressure increased during time in PHN and was normalized by treatment with ACE inhibitor and combined therapy. Even at the high dose lisinopril failed to reduce proteinuria. Simvastatin only partially affected proteinuria. However, combining lisinopril with simvastatin had a remarkable antiproteinuric effect, such that at 10 months the urinary proteins were comparable to pre-treatment values and significantly lower than either the vehicle or lisinopril groups. Hypercholesterolemia of PHN rats was limited by combined therapy, and a positive correlation was found between serum cholesterol and proteinuria. Renal function was only partially ameliorated by simvastatin but significantly improved by combined therapy. Drug combination significantly limited glomerulosclerosis, tubular damage and interstitial inflammation, compared to vehicle or drugs alone. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) mRNA in PHN kidneys was not affected by lisinopril, it was inhibited by 30% after simvastatin, and almost completely normalized by lisinopril plus simvastatin.
These data suggest that a combined ACE inhibitor and statin approach could represent a therapeutic option for patients with advanced renal disease in whom ACE inhibitors alone fail to lower proteinuria and injury to any substantial extent.
在几乎所有疾病进展模型中，疾病诱导后立即给予血管紧张素转换酶（ACE）抑制剂治疗均能一致地预防蛋白尿。但这不一定适用于蛋白尿性肾病患者，他们可能在疾病进程较晚时才被转诊。在此，我们使用严重的被动型海曼肾炎（PHN）大鼠模型（其可能模拟人类膜性肾病的晚期阶段），来研究单独使用ACE抑制剂或与HMG CoA还原酶抑制剂（他汀类药物）联合使用时的反应，该他汀类药物独立于降胆固醇作用，可影响参与炎症和纤维化过程的通路。治疗在动物出现大量蛋白尿和肾损伤时开始。
在静脉注射兔抗FX1A抗体7天后，通过单侧肾切除加速PHN进程。4个月后，当出现大量蛋白尿和肾损伤时，将大鼠分为五组，每日经口给予：赋形剂；赖诺普利40mg/L；赖诺普利400mg/L；辛伐他汀2mg/kg，每日两次；或赖诺普利40mg/L加辛伐他汀。6只正常大鼠作为对照。在10个月时处死动物。
到研究结束时，赋形剂组有3只PHN大鼠死亡，40mg/L赖诺普利组有4只死亡，400mg/L组有2只死亡，而所有接受辛伐他汀或联合治疗的大鼠均存活。PHN期间血压随时间升高，ACE抑制剂治疗和联合治疗可使其恢复正常。即使是高剂量的赖诺普利也未能降低蛋白尿。辛伐他汀仅部分影响蛋白尿。然而，赖诺普利与辛伐他汀联合使用具有显著的抗蛋白尿作用，以至于在10个月时尿蛋白与治疗前值相当，且显著低于赋形剂组或赖诺普利组。联合治疗限制了PHN大鼠的高胆固醇血症，且发现血清胆固醇与蛋白尿之间存在正相关。辛伐他汀仅部分改善肾功能，但联合治疗使其显著改善。与赋形剂或单独用药相比，联合用药显著限制了肾小球硬化、肾小管损伤和间质炎症。PHN肾中单核细胞趋化蛋白-1（MCP-1）mRNA的上调不受赖诺普利影响，辛伐他汀使其抑制30%，而赖诺普利加辛伐他汀几乎完全使其恢复正常。
这些数据表明，对于单独使用ACE抑制剂未能在很大程度上降低蛋白尿和损伤的晚期肾病患者，ACE抑制剂与他汀类药物联合使用可能是一种治疗选择。
