Novel therapeutic targets for diabetic nephropathy.

糖尿病肾病的新治疗靶点。

基本信息

  • 批准号:
    17590828
  • 负责人:
  • 金额:
    $ 2.24万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    2005
  • 资助国家:
    日本
  • 起止时间:
    2005 至 2006
  • 项目状态:
    已结题

项目摘要

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.
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。

项目成果

期刊论文数量(26)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients.
  • DOI:
    10.1016/j.diabres.2006.09.004
  • 发表时间:
    2007-06
  • 期刊:
  • 影响因子:
    5.1
  • 作者:
    R. Yoshikawa;J. Wada;K. Seiki;Takashi Matsuoka;S. Miyamoto;Kenji Takahashi;S. Ota;K. Taniai-
  • 通讯作者:
    R. Yoshikawa;J. Wada;K. Seiki;Takashi Matsuoka;S. Miyamoto;Kenji Takahashi;S. Ota;K. Taniai-
The association of C-reactive protein with an oxidative metabolite of LDL and its implicationin atherosclerosis
C反应蛋白与LDL氧化代谢物的关联及其在动脉粥样硬化中的意义
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Tabuchi M;Inoue K;Usui-Kataoka H;Kobayashi K;Teramoto M;Takasugi K;Shikata K;Yamamura M;Ando K;Nishida K;Kasahara J;Kume N;Lopez LR;Mitsudo K;Nobuyoshi M;Yasuda T;Kita T;Makino H;Matsuura E
  • 通讯作者:
    Matsuura E
Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1523-31.Epub2007Aug8.
Edaravone 模拟 1-磷酸鞘氨醇诱导的人微血管内皮细胞内皮屏障增强。
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Omori K;Shikata Y;Sarai K;Watanabe N;Wada J;Goda N;Kataoka N;Shikata K;Makino H.
  • 通讯作者:
    Makino H.
Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions.
  • DOI:
    10.1681/asn.2004111011
  • 发表时间:
    2005-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kosuke Yozai;K. Shikata;Motofumi Sasaki;A. Tone;S. Ohga;H. Usui;S. Okada;J. Wada;Ryo Nagase-Ryo-Nagas
  • 通讯作者:
    Kosuke Yozai;K. Shikata;Motofumi Sasaki;A. Tone;S. Ohga;H. Usui;S. Okada;J. Wada;Ryo Nagase-Ryo-Nagas
Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms
  • DOI:
    10.2337/db05-1285
  • 发表时间:
    2006-06-01
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Okada, Tatsuo;Wada, Jun;Makino, Hirofumi
  • 通讯作者:
    Makino, Hirofumi
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SHIKATA Kenichi其他文献

SHIKATA Kenichi的其他文献

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{{ truncateString('SHIKATA Kenichi', 18)}}的其他基金

Development of the novel therapeutic strategy for diabetic nephropathy through anti-inflammatory effects.
通过抗炎作用开发糖尿病肾病的新治疗策略。
  • 批准号:
    21591031
  • 财政年份:
    2009
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Exploratory research to development of novel therapeutic strategy for diabetic nephropathy
糖尿病肾病治疗新策略的探索性研究
  • 批准号:
    19590952
  • 财政年份:
    2007
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Role of Macrophage in the pathogenesis of diabetic nephropathy and novel therapeutic target.
巨噬细胞在糖尿病肾病发病机制中的作用及新的治疗靶点。
  • 批准号:
    15590850
  • 财政年份:
    2003
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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
  • 财政年份:
    2001
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Application of anti-adhesion molecule therapy for glomerulonephritis -Effects of sulfated oligosaccharides as selectin-blocking agents-
抗粘连分子疗法在肾小球肾炎中的应用-硫酸化寡糖作为选择素阻断剂的作用-
  • 批准号:
    11671036
  • 财政年份:
    1999
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Mechanism of inflammatory cell infiltration in the kidney tissue of glomerulonephritis and diabetic nephropathy. -Elucidation of the role of cell adhesion molecules and development of therapeutic drugs.-
肾小球肾炎和糖尿病肾病肾组织炎症细胞浸润机制。
  • 批准号:
    06671141
  • 财政年份:
    1994
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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