期刊
NEPHRON EXPERIMENTAL NEPHROLOGY
卷 115, 期 3, 页码 E69-E79出版社
KARGER
DOI: 10.1159/000313832
关键词
Renin-angiotensin-aldosterone system; Calpain; Angiotensin II receptor blockers; Streptozotocin-induced diabetic nephropathy
资金
- Ministry of Education, Science, Sports and Culture [10670988, 12671032]
- Novartis Pharmaceuticals
Background/Aims: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. Methods and Results: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-kappa B, as shown by an increase in the expression of the p65 subunit of NF-kappa B and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. Conclusion: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy. Copyright (C) 2010 S. Karger AG, Basel
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