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。

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671116/
• 关键词: Diabetic nephropathy; Macrophage; Kidney; Inflammation; ICAM-1; Glomerulus; Interstitium; TGF-β; ICAM-1; サイトカイン; DNAアレイ; 糖尿病; 腎臓; コラーゲン; DNA

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。我们之前证明了细胞间粘附分子(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，我们用链脲佐菌素诱导ICAM-1缺陷（ICAM-1(-/-)）小鼠和ICAM-1（+/+）小鼠患糖尿病，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明显低于糖尿病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，我们还研究了肾脏中的基因表达谱。利用DNA微阵列系统对这些小鼠进行检测。促炎基因在糖尿病ICAM-1（+/+）小鼠肾脏中表达上调，而与ICAM-1（+/+）小鼠相比，这些基因在糖尿病ICAM-1（-/-）小鼠肾脏中的表达水平降低。这些结果表明，ICAM-1在糖尿病肾病的发病机制中起关键作用。

项目成果

Yamashita T, Shikata K, Matsuda M, Okada S, Ogawa D, Sugimoto H, Wada J, Makino H.: "Beraprost sodium, prostacyclin analogue, attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats."Dia

Yamashita T、Shikata K、Matsuda M、Okada S、Okawa D、Sugimoto H、Wada J、Makino H.：“贝前列素钠、前列环素类似物，通过调节糖尿病大鼠的 ecNOS 表达来减轻肾小球过度滤过和肾小球巨噬细胞浸润。”Dia

Hiragushi K, Wada J, Eguchi J, Matsuoka T, Yasuhara A, Hashimoto I, Yamashita T, Hida K, Nakamura Y, Shikata K, Minamino N, Kangawa K, Makino H.: "The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic ra

Hiragushi K、Wada J、Eguchi J、Matsuoka T、Yasuhara A、Hashimoto I、Yamashita T、Hida K、Nakamura Y、Shikata K、Minamino N、Kangawa K、Makino H.：“肾上腺髓质素和受体在肾小球超滤过中的作用

Ymashita T, Shikata K et al.: "Beraprost sodium, prostacyclin analogue, attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats."Diabetes Res Clin Pract. 57. 149-161 (2002)

Ymashita T、Shikata K 等人：“贝前列素钠，前列环素类似物，通过调节糖尿病大鼠的 ecNOS 表达来减轻肾小球过度滤过和肾小球巨噬细胞浸润。”糖尿病研究临床实践。

Ogawa D, Shikata K et al.: "Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction."J Biol Chem. 16. 2085-2090 (2004)

Okawa D、Shikata K 等人：“脑苷脂磺基转移酶缺乏可改善输尿管梗阻后肾脏中 L-选择素依赖性单核细胞浸润。”J Biol Chem。

Okada S, Shikata K et al.: "Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes,"Diabetes. 52. 2586-2593 (2003)

Okada S、Shikata K 等人：“细胞间粘附分子 1 缺陷的小鼠在诱导糖尿病后能够抵抗肾损伤”，糖尿病。