Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats

被引:11
作者
Fredersdorf, Sabine [1 ]
Weil, Joachim
Ulucan, Coskun
Birner, Christoph
Buettner, Roland
Schubert, Thomas
Boeger, Carsten A.
Debl, Kurt
Muders, Frank
Riegger, Guenter A.
Luchner, Andreas
机构
[1] Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany
[2] Univ Regensburg, Inst Pathol, D-93053 Regensburg, Germany
[3] Univ Klinikum Schleswig Holstein, Med Klin 2, D-23538 Lubeck, Germany
关键词
diabetes mellitus; kidney glomerulosclerosis; vasopeptidase inhibition;
D O I
10.1007/s00210-007-0147-9
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Inhibition of the renin angiotensin aldosterone system (RAAS) produces protective effects on cardio-renal injury in type 2 diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool, acting by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type 2 diabetes as compared to angiotensin converting enzyme inhibition (ACE-I). Zucker diabetic fatty rats aged 13 weeks were treated with either VPI (AVE7688, ZDF-VPI, n=8) or ACE-I (Ramipril, ZDF-ACE-I, n=7) or placebo (ZDF, n-8). Heterozygous rats served as non-diabetic controls (Ctr, n=8). Both treatments led to a similar decrease in blood pressure. After 10 weeks of treatment, ZDF developed marked albuminuria. The latter was significantly attenuated in ZDF-VPI as compared to ZDF and ZDF-ACE-I. Renal histology revealed a significant expansion in the glomerular tuft area in all ZDF groups. However, expression of glomerular desmin, which has been recognized as a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to Ctr. Desmin was reduced in ZDF-VPI but not in animals treated with ACE-I. There was a correlation between albumin excretion and desmin-positive glomerular area. In experimental type 2 diabetes, albuminuria correlates to podocyte damage. These hallmarks of diabetic nephropathy are attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest that podocyte damage is an early critical step in the progression of diabetic nephropathy, and that VPI is a promising pharmacological tool in the treatment of diabetic renal disease.
引用
收藏
页码:95 / 103
页数:9
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