Ohtomo Shuichi, Ito Masaki, Izuhara Yuko, Van Ypersele De Strihou Charles, Miyata Toshio
Institute of Medical Sciences, Tokai University, Kanagawa, Japan.
Nephrology (Carlton). 2008 Dec;13(6):517-21. doi: 10.1111/j.1440-1797.2008.00929.x. Epub 2008 Mar 17.
Antihypertensive agents inhibiting the renin-angiotensin system (RAS), such as angiotensin II type 1 receptor blockers (ARB), are now part of the standard treatment of patients with diabetic nephropathy, regardless of the presence of systemic hypertension. Whether ARB achieve better renoprotection than other RAS-independent antihypertensive drugs has been an issue of controversy. Several lines of large clinical studies provided better renoprotection of ARB. However, a recent meta-analysis argued against additional benefits of ARB beyond blood pressure. We generated a novel mouse model of diabetic nephropathy; that is, megsin/receptor for advanced glycation end products/inducible nitric oxide synthase triple transgenic mice. This model is normotensive but progressively develops severe diabetic nephropathy that resembles those observed in humans.
In the present study, we tested whether olmesartan (ARB) achieves better renoprotection than amlodipine (calcium channel blocker). Drug treatment was initiated at the age of 6 weeks and lasted for 12 weeks.
This model develops significant glomerular lesions and albuminuria even at the age of 5 weeks. Despite equal blood pressure lowering, only olmesartan suppressed the progression of albuminuria. Neither olmesartan nor amlodipine modified histological lesions.
Proteinuria and its reduction are known to predict the progression of diabetic nephropathy. Our results support the additional benefit of ARB beyond blood pressure lowering.
抑制肾素-血管紧张素系统（RAS）的抗高血压药物，如血管紧张素II 1型受体阻滞剂（ARB），现已成为糖尿病肾病患者标准治疗的一部分，无论是否存在全身性高血压。ARB是否比其他不依赖RAS的抗高血压药物具有更好的肾脏保护作用一直存在争议。多项大型临床研究表明ARB具有更好的肾脏保护作用。然而，最近的一项荟萃分析反对ARB在降低血压之外还有其他益处的观点。我们构建了一种新型糖尿病肾病小鼠模型，即 megsin/晚期糖基化终产物受体/诱导型一氧化氮合酶三转基因小鼠。该模型血压正常，但会逐渐发展为严重的糖尿病肾病，类似于人类观察到的情况。
在本研究中，我们测试了奥美沙坦（ARB）是否比氨氯地平（钙通道阻滞剂）具有更好的肾脏保护作用。药物治疗在6周龄时开始，持续12周。
该模型即使在5周龄时就出现了明显的肾小球病变和蛋白尿。尽管血压降低程度相同，但只有奥美沙坦抑制了蛋白尿的进展。奥美沙坦和氨氯地平均未改善组织学病变。
蛋白尿及其减少已知可预测糖尿病肾病的进展。我们的结果支持ARB在降低血压之外还有其他益处的观点。
