Novel therapeutic targets for diabetic nephropathy.

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。为了寻找治疗糖尿病肾病的新靶点，我们在ICAM-1(-/-)缺陷(ICAM-1(-/-))小鼠和ICAM-1(+/+)小鼠诱导糖尿病或5/6肾切除，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(-/-)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。骨桥蛋白、CCK和清道夫受体A等基因在糖尿病或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。与野生型小鼠相比，清道夫受体A基因缺陷小鼠在双硅酸盐诱导后蛋白尿和肾脏损伤减少。与野生型小鼠相比，CCK受体缺陷小鼠的肾脏损伤在5/6肾切除后得到改善。我们的结果表明微炎症参与了糖尿病肾病的发病机制。CCK、清道夫受体A和骨桥蛋白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. To find a novel therapeutic target for diabetic nephropathy, 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 tissue 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. Several genes including osteopontin, cholecystokinin (CCK) and scavenger receptor A are up-regulated in the kidneys of diabetic or 5/6 nephretomized ICAM-1(+/+) mice, while the expression levels of these genes were decreased in diabetic or 5/6 nephrectomized ICAM-1(-/-) mice as compared to ICAM-1(+/+) mice. Scavenger receptor A deficient mice revealed diminished albuminuria and renal injuries after induction of dianetes as compared with wild type mice. Renal injuries were ameliorated in CCK-receptor deficient mice after 5/6 nephrectomy as compared with wild type mice. Our results indicate that microinflammation is involved in the pathogenesis of diabetic nephropathy. CCK, scavenger receptor A and osteopontin may be novel therapeutic target for diabetic nephropathy.