Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker
Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker
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DOI：
10.1161/01.hyp.0000222003.28517.99
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发表时间：
2006-06-01
期刊：
影响因子：
8.3
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Nagase, Miki;Shibata, Shigeru;Fujita, Toshiro
最近的临床研究表明，蛋白尿是高血压患者肾脏和心血管并发症的一个关键预后因素。然而，高血压蛋白尿的发病机制尚不清楚。足细胞构成肾小球的最后过滤屏障，其功能障碍可能在蛋白尿中起关键作用。在本研究中，我们研究了参与足细胞损伤的达尔盐高血压大鼠，动物模型容易患高血压性肾小球硬化症，并探讨了抑制醛固酮的影响。给4周龄的Dahl盐耐受和盐敏感大鼠喂食0.3%或8.0%NaCl饮食。用选择性醛固酮阻断剂依普利酮（1.25 mg/g饲料）或肼苯哒嗪（0.5 mmol/L）处理一些盐负荷的Dahl盐敏感大鼠。6周后，盐负荷的达尔盐敏感大鼠发展为严重的高血压、蛋白尿和肾小球硬化。nephrin，狭缝隔膜的组成部分，免疫染色减弱，而受损的足细胞标志物结蛋白和B7-1的表达上调的盐负荷达尔盐敏感大鼠的肾小球。电镜分析显示足细胞足突消失。在Dahl盐敏感大鼠中，足细胞早在盐负荷2周时就已受损，此时蛋白尿适度增加。依普利酮和肼苯哒嗪部分降低全身血压，通过间接和直接方法在盐负荷达尔盐敏感大鼠，但只有依普利酮显着改善足细胞损伤和延缓蛋白尿和肾小球硬化症的进展。我们的研究结果表明，足细胞损伤的基础Dahl盐高血压大鼠的肾小球病变和依普利酮抑制醛固酮是保护对足细胞损伤，蛋白尿，肾小球硬化症在这种高血压模型。
Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.