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。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，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尚不清楚。巨噬细胞的积累和白细胞粘附分子和趋化因子的过度表达在糖尿病人肾脏组织中是突出的。我们之前证明细胞间粘附分子(ICAM)- 1介导巨噬细胞浸润到糖尿病肾脏。在本研究中，为了研究巨噬细胞在糖尿病肾病中的作用并寻找新的治疗靶点，我们在ICAM-1缺陷（ICAM-1(-/-)）小鼠和ICAM-1（+/+）小鼠中诱导糖尿病或5/6肾切除术，并在6个月的时间内观察肾脏病理。与ICAM-1（+/+）小鼠相比，糖尿病ICAM-1（-/-）小鼠或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均明显受到抑制。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。促炎因子包括骨桥蛋白在糖尿病或5/6肾切除的ICAM-1（+/+）小鼠的肾脏中上调，而与ICAM-1（+/+）小鼠相比，这些基因在糖尿病或5/6肾切除的ICAM-1（-/-）小鼠的肾脏中表达水平降低。这些基因可能成为糖尿病肾病治疗的新靶点。

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.