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

糖尿病肾病是终末期肾功能衰竭的主要原因。一些机制，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β的过度表达，被认为参与了糖尿病肾病的发病机制。然而，炎症过程在糖尿病微血管并发症发病机制中的意义还知之甚少。巨噬细胞聚集、白细胞黏附分子和趋化因子的过度表达在糖尿病人肾组织中显著。我们先前证明了细胞间黏附分子(ICAM)-1介导巨噬细胞向糖尿病肾脏的渗透。为了探讨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基因缺陷(ICAM-1(-/-))小鼠和ICAM-1(+/+)小鼠糖尿病，并观察了6个月的肾脏病理变化。与ICAM-1(+/+)小鼠相比，糖尿病ICAM-1(-/-)小鼠巨噬细胞的浸润明显受到抑制。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著低于糖尿病ICAM-1(+/+)小鼠。此外，糖尿病ICAM-1(-/-)小鼠肾小球中转化生长因子-β和IV型胶原的表达也受到抑制。此外，我们还研究了肾脏中的基因表达谱。这些小鼠使用DNA微阵列系统。与ICAM-1(+/+)小鼠相比，糖尿病ICAM-1(-/-)小鼠肾脏促炎基因表达上调，而这些基因的表达水平降低。这些结果提示ICAM-1在糖尿病肾病的发病机制中起重要作用。

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.