Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes
Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes
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DOI：
10.2337/diabetes.47.3.450
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发表时间：
1998-03-01
期刊：
影响因子：
7.7
通讯作者：
Remuzzi, G
中科院分区：
文献类型：
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作者：
Benigni, A;Colosio, W;Remuzzi, G
慢性肾病与内皮素（ET）-1的肾脏合成增强有关。最近的一项研究表明，在糖尿病大鼠发病时给予ET 1受体拮抗剂可预防肾损伤的发生。在此，我们研究了当动物已经出现蛋白尿时，给予链脲佐菌素糖尿病大鼠非选择性ETA/ETB受体拮抗剂PD 142，893是否具有肾保护作用。将PD 142，893的作用与已知在实验性糖尿病和人类糖尿病中延缓进行性肾病的ACE抑制剂赖诺普利的作用进行比较，PD 142，893使糖尿病大鼠的全身血压正常化，减少尿蛋白和白蛋白排泄，并改善肾血流量，但它不影响对照大鼠的这些参数，赖诺普利的肾脏保护作用与PD 142，893相当，但赖诺普利控制全身血压的效果更好，北方印迹分析显示糖尿病大鼠肾脏中Eg-1基因表达上调。这两种治疗方法均能显著降低肾脏ET-1基因的过度表达，提示ET-1是糖尿病肾损害的一个重要介质，并提示ET受体拮抗剂可能成为治疗进展性糖尿病肾病的一种新的治疗手段。
Chronic nephropathies are associated with enhanced renal synthesis of endothelin (ET)-1. A recent study demonstrated that an ET, receptor antagonist given to diabetic rats at the moment of disease induction prevented the development of renal injury, Here we investigated whether an unselective ETA/ETB receptor antagonist, PD 142,893, was renoprotective when given to streptozotocin diabetic rats when animals were already proteinuric. The effect of PD 142,893 was compared with that of an ACE inhibitor, lisinopril, known to retard progressive renal disease in experimental and human diabetes, PD 142,893 normalized systemic blood pressure, reduced urinary protein and albumin excretion, and ameliorated renal blood flow in diabetic rats, but it did not affect such parameters in control rats, Lisinopril had a renoprotective effect comparable to PD 142,893, although lisinopril controlled systemic blood pressure better, Northern blot analysis of ET-1 mRNA revealed upregulation of Eg-l gene in the diabetic kidney, Similar results were obtained by in situ hybridization in glomeruli and tubuli of diabetic rats, Both treatments remarkably attenuated exaggerated renal ET-1 gene expression, These data suggest that ET-1 is a contributory mediator of kidney damage in diabetes and indicate that ET receptor antagonists may represent a new therapeutic mean for treatment of progressive diabetic nephropathy.