Efficacy of aliskiren, compared with angiotensin II blockade, in slowing the progression of diabetic nephropathy in db/db mice: should the combination therapy be a focus?
Efficacy of aliskiren, compared with angiotensin II blockade, in slowing the progression of diabetic nephropathy in db/db mice: should the combination therapy be a focus?
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发表时间：
2015-05
影响因子：
2.2
通讯作者：
Guangyu Zhou;Xia Liu;A. Cheung;Yufeng Huang
中科院分区：
文献类型：
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作者：
Guangyu Zhou;Xia Liu;A. Cheung;Yufeng Huang
虽然密集使用血管紧张素II阻断剂（ACEI或ARB），但糖尿病肾病进展是常见的。血管紧张素II阻滞剂常伴随着肾素生成的反馈性增加。因此，我们研究了阿利吉仑（一种直接的肾素抑制剂）是否比血管紧张素II阻滞剂具有更好的肾保护作用，以及在ACEI或ARB中加入阿利吉仑是否会提高减缓糖尿病肾小球硬化进展的疗效。未治疗的db/db小鼠在第18周至第22周之间发生进行性系膜基质扩张和白蛋白尿，与WT-1免疫阳性足细胞和nephrin和podocin产生的减少以及结蛋白和B7-1产生的诱导和TGF β 1、派-1、纤连蛋白和IV型胶原的肾表达相关。30 mg/kg/d阿利吉仑治疗可抑制db/db小鼠中观察到的白蛋白尿和肾纤维化标志物的增加以及足细胞损伤的变化。值得注意的是，阿利吉仑的治疗效果与最大有效剂量单独给药的依那普利或缬沙坦相似。联合治疗可使db/db小鼠减少10% ~ 16.6%，但不能进一步减轻肾纤维化和足细胞损伤，但可进一步减少白蛋白尿、肾组织TNFα、Nox 2和p47 phox的产生以及肾组织炎症和氧化应激标志物MCP-1和丙二醛的水平。这些结果表明，阿利吉仑，依那普利和缬沙坦在减缓糖尿病肾病进展方面同样有效。使用阿利吉仑和ACEI/ARB联合治疗可能不会得到强烈支持。
Although the intensive use of angiotensin II blockade (ACEI or ARB), progression of diabetic nephropathy is common. A feedback increase in renin production often accompanies angiotensin II blockade. We therefore examined whether aliskiren, a direct renin inhibitor, confers better renoprotection than angiotensin II blockade and whether the addition of aliskiren to an ACEI or ARB would enhance the efficacy in slowing the progression of glomerulosclerosis in diabetes. Untreated db/db mice developed progressive mesangial matrix expansion and albuminuria between weeks 18 and 22, associated with reduction of WT-1 immunopositive podocytes and nephrin and podocin production and induction of desmin and B7-1 generation and renal expression of TGFß1, PAI-1, fibronectin and type IV collagen. Treatment with aliskiren at 30 mg/kg/d inhibited the increases in albuminuria and markers of renal fibrosis and the changes that are indicative of podocyte injury seen in the db/db mice. Notably, the therapeutic effect of aliskiren was similar to that of either enalapril or valsartan given alone at maximally effective doses. Combined therapy caused the loss of 10% ~ 16.6% of db/db mice, yielded no further reduction in renal fibrosis and podocyte injury but further reduced albuminuria and renal production of TNFα, Nox2 and p47phox and urine MCP-1 and malondialdehyde levels, the markers of renal inflammation and oxidative stress. These results suggest that aliskiren, enalapril and valsartan are equally effective in slowing the progression of diabetic nephropathy. The use of combination therapy with aliskiren and ACEI/ARB may not be strongly supported.