Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice
Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice
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DOI：
10.1152/ajprenal.00292.2011
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发表时间：
2012-02-01
影响因子：
4.2
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
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作者：
Zhang, Ming-Zhi;Wang, Suwan;Harris, Raymond C.
Zhang MZ，Wang S，Yang S，Yang H，Fan X，Takahashi T，Harris RC.血压和肾素-血管紧张素系统在eNOS（-/-）db/db小鼠糖尿病肾病（DN）发展中的作用美国肾脏生理学杂志302：F433-F438，2012年。首次发表于2011年11月23日; doi：10.1152/ajprenal.00292.2011.-随机临床试验已经清楚地表明，抑制肾素-血管紧张素系统（RAS）将减缓糖尿病肾病的进展速度，但关于所观察到的有益效果是否不仅仅是控制血压的结果仍然存在争议。在II型糖尿病模型db/db小鼠（eNOS（-/-）db/db）中缺失eNOS诱导加速性肾病，并提供了人糖尿病肾病的极好模型。正如在II型糖尿病中常见的那样，eNOS（-/-）db/db小鼠的血压中度升高。为了确定血压升高本身与RAS在介导疾病进展中的额外有害作用的作用，将8周龄eNOS（-/-）db/db小鼠随机分为三组：载体、血管紧张素转换酶抑制剂（ACEI）卡托普利治疗或“三联疗法”治疗（肼屈嗪、瑞司匹林、氢氯噻嗪），并在治疗12周后对动物实施安乐死。血压降低到与ACE抑制剂或三联疗法相当的水平。虽然两种治疗方案均减少了糖尿病肾病的发生，但ACE抑制剂可更显著地减少蛋白尿、肾小球硬化、肾小管间质损伤标志物、巨噬细胞浸润和炎症标志物。因此，该动物模型表明，虽然血压控制具有重要作用，但RAS阻断在减缓糖尿病肾病进展方面提供了额外的益处。
Zhang MZ, Wang S, Yang S, Yang H, Fan X, Takahashi T, Harris RC. Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS(-/-) db/db mice. Am J Physiol Renal Physiol 302: F433-F438, 2012. First published November 23, 2011; doi:10.1152/ajprenal.00292.2011.-Randomized clinical trials have clearly shown that inhibition of the renin-angiotensin system (RAS) will slow the rate of progression of diabetic nephropathy, but controversy remains about whether the observed beneficial effects result from more than control of blood pressure. Deletion of eNOS in a model of type II diabetes, db/db mice (eNOS(-/-) db/db), induces an accelerated nephropathy and provides an excellent model of human diabetic nephropathy. As is frequently seen in type II diabetes, blood pressure is moderately elevated in eNOS(-/-) db/db mice. To determine the role of elevated blood pressure per se vs. additional deleterious effects of the RAS in mediation of disease progression, 8-wk-old eNOS(-/-) db/db mice were randomly divided into three groups: vehicle, treatment with the angiotensin-converting enzyme inhibitor (ACEI) captopril, or treatment with "triple therapy" (hydralazine, resperine, hydrocholorothiazide), and the animals were euthanized after treatment for 12 wk. Blood pressure was reduced to comparable levels with ACE inhibition or triple therapy. Although both treatment regimens decreased development of diabetic nephropathy, ACE inhibition led to more profound reductions in albuminuria, glomerulosclerosis, markers of tubulointerstitial injury, macrophage infiltration, and markers of inflammation. Therefore, this animal model suggests that while there is an important role for blood pressure control, RAS blockade provides additional benefits in slowing the progression of diabetic nephropathy.