Ivanovski Ognen, Szumilak Dorota, Nguyen-Khoa Thao, Nikolov Igor G, Joki Nobuhiko, Mothu Nadya, Maizel Julien, Westenfeld Ralf, Ketteler Marcus, Lacour Bernard, Drüeke Tilman B, Massy Ziad A
Institut National en Santé et Recherche Médicale Unit 845, Paris, France.
J Urol. 2008 Apr;179(4):1631-6. doi: 10.1016/j.juro.2007.11.042. Epub 2008 Mar 4.
Patients with a surgically reduced renal mass are at increased risk for progressive renal failure, which often requires renal replacement therapy or kidney transplantation. We investigated the effects of simvastatin supplementation on uremia enhanced atherosclerosis and vascular calcification in apoE(-/-) (apolipoprotein E deficient) mice (Charles Rivers Laboratories, Wilmington, Massachusetts) with or without superimposed chronic kidney disease.
The mice were randomly assigned to 4 groups, including 2 groups with normal renal function (simvastatin vs control in 13 mice) and the other 2 with surgically created chronic kidney disease (simvastatin vs control in 18). Simvastatin (100 mg/kg) was administered by daily oral gavage for 4 weeks.
Simvastatin treatment did not prevent uremia accelerated atherosclerosis in chronic kidney disease apoE(-/-) mice, nor did it retard atherosclerosis progression in control nonchronic kidney disease mice. However, aortic plaques in simvastatin treated chronic kidney disease mice showed significantly less calcification than those in controls with chronic kidney disease (p <0.03). In addition, the increase of aortic nitrotyrosine staining in mice with chronic kidney disease was prevented by simvastatin treatment (p <0.02). Serum total cholesterol was increased to a similar extent in the 2 chronic kidney disease groups compared with that in the nonchronic kidney disease groups. The beneficial effect of simvastatin on uremia enhanced vascular calcification in apoE(-/-) mice with chronic kidney disease was observed despite the absence of changes in uremia accelerated atherosclerosis progression, serum total cholesterol levels or osteopontin and alkaline phosphatase expression.
Our observation opens the possibility of a cholesterol independent action of statins on vascular calcification via a decrease in oxidative stress.
接受手术切除肾肿块的患者发生进行性肾衰竭的风险增加，而这通常需要肾脏替代治疗或肾移植。我们研究了补充辛伐他汀对伴有或不伴有叠加慢性肾脏病的载脂蛋白E基因敲除（apoE(-/-)）小鼠（查尔斯河实验室，马萨诸塞州威尔明顿）的尿毒症性动脉粥样硬化和血管钙化的影响。
将小鼠随机分为4组，包括2组肾功能正常的小鼠（辛伐他汀组13只与对照组）以及另外2组通过手术造成慢性肾脏病的小鼠（辛伐他汀组18只与对照组）。通过每日口服灌胃给予辛伐他汀（100mg/kg），持续4周。
辛伐他汀治疗未能预防慢性肾脏病apoE(-/-)小鼠的尿毒症加速动脉粥样硬化，在对照的非慢性肾脏病小鼠中也未延缓动脉粥样硬化进展。然而，辛伐他汀治疗的慢性肾脏病小鼠的主动脉斑块钙化明显少于慢性肾脏病对照组（p<0.03）。此外，辛伐他汀治疗可预防慢性肾脏病小鼠主动脉硝基酪氨酸染色增加（p<0.02）。与非慢性肾脏病组相比，2个慢性肾脏病组的血清总胆固醇升高程度相似。尽管尿毒症加速动脉粥样硬化进展、血清总胆固醇水平或骨桥蛋白及碱性磷酸酶表达未发生变化，但仍观察到辛伐他汀对伴有慢性肾脏病的apoE(-/-)小鼠的尿毒症性血管钙化具有有益作用。
我们的观察结果提示他汀类药物可能通过降低氧化应激对血管钙化发挥不依赖胆固醇的作用。
