Role of Macrophage in the pathogenesis of diabetic nephropathy revealed by ICAM-1 deficient mice.

ICAM-1 缺陷小鼠揭示巨噬细胞在糖尿病肾病发病机制中的作用。

基本信息

批准号：
13671116
负责人：
SHIKATA Kenichi
金额：
$ 2.24万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of macrophage in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. Moreover, we investigated the gene expression profiles in the kidneys. of these mice using DNA microarray system. Proinflammatory genes are up-regulated in the kidneys of diabetic ICAM-1(+/+) mice, while the expression levels of these genes were decresased in diabetic ICAM-1(-/-) mice as compared to ICAM-1(+/+) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.

糖尿病肾病是终末期肾衰竭的主要原因。据信，糖尿病肾病的发病机制涉及多种机制，包括蛋白激酶 C 的激活、晚期糖基化终产物和转化生长因子 (TGF)-β 的过度表达。然而，人们对炎症过程在糖尿病微血管并发症发病机制中的重要性知之甚少。糖尿病人肾组织中巨噬细胞的积累以及白细胞粘附分子和趋化因子的过度表达是显着的。我们之前证明细胞间粘附分子（ICAM）-1 介导巨噬细胞浸润糖尿病肾。在本研究中，为了研究巨噬细胞在糖尿病肾病中的作用，我们用链脲佐菌素诱导 ICAM-1 缺陷型 (ICAM-1(-/-)) 小鼠和 ICAM-1(+/+) 小鼠患糖尿病，并检查了巨噬细胞在糖尿病肾病中的作用。 6个月期间的肾脏病理学。与ICAM-1(+/+)小鼠相比，糖尿病ICAM-1(-/-)小鼠的巨噬细胞浸润明显受到抑制。糖尿病ICAM-1(-/-)小鼠的尿白蛋白排泄、肾小球肥大和系膜基质扩张显着低于糖尿病ICAM-1(+/+)小鼠。此外，糖尿病ICAM-1(-/-)小鼠肾小球中TGF-β和IV型胶原的表达也受到抑制。此外，我们研究了肾脏中的基因表达谱。使用 DNA 微阵列系统对这些小鼠进行研究。糖尿病 ICAM-1(+/+) 小鼠肾脏中的促炎基因上调，而与 ICAM-1(+/) 小鼠相比，糖尿病 ICAM-1(-/-) 小鼠中这些基因的表达水平降低+) 老鼠。这些结果表明ICAM-1在糖尿病肾病的发病机制中发挥着重要作用。