Role of Macrophage in the pathogenesis of diabetic nephropathy and novel therapeutic target.

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，寻找新的治疗靶点，我们建立了ICAM-1基因缺陷(ICAM-1(-/-))小鼠和ICAM-1(+/+)小鼠的糖尿病模型和5/6肾切除模型，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(-/-)小鼠和5/6肾切除ICAM-1(-/-)小鼠的巨噬细胞浸润、蛋白尿和肾组织损伤明显受到抑制。我们利用DNA微阵列系统研究了这些小鼠肾脏的基因表达谱。包括骨桥蛋白在内的促炎基因在糖尿病或5/6肾切除ICAM-1(+/+)小鼠肾脏中表达上调，而这些基因在糖尿病或5/6肾切除ICAM-1(-/-)小鼠肾脏中的表达水平低于ICAM-1(+/+)小鼠。这些基因可能成为治疗糖尿病肾病的新靶点。

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 and find a novel therapeutic target, we induced diabetes or 5/6 nepphrectomy in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice and examined the renal pathology over a period of 6 months. The infiltration of macrophages, albuminuria anc renal tiossue injuries were markedly suppressed in diabetic ICAM-1(-/-) mice or 5/6 nephrectomized ICAM-1(-/-) mice compared with ICAM-1(+/+) mice. We investigated the gene expression profiles in the kidneys of these mice using DNA microarray system. Proinflammatory geses including osteopontin are up-regulated in the kidneys of diabetic or 5/6 nephrectomized ICAM-1(+/+) mice, while the expression levels of these genes were decresased in diabetic or 5/6nephrectomized ICAM-1(-/-) mice as compared to ICAM-1(+/+) mice. These genes might be novel targets for the therapy of diabetic nephropathy.