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首页> 外文学位 >Rac GTPase-mediated NADPH oxidase redox signaling in hyperhomocysteinemic glomerular injury.
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Rac GTPase-mediated NADPH oxidase redox signaling in hyperhomocysteinemic glomerular injury.

机译：Rac GTPase介导的高同型半胱氨酸肾小球损伤中的NADPH氧化酶氧化还原信号。

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摘要

Hyperhomocysteinemia (hHcys) is emerging as a critical pathogenic factor in the progression of end stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Previous studies in our laboratory have demonstrated that Hcys acutely increases the production of superoxide (O2·-) via NADPH oxidase and thereby stimulates the formation of tissue inhibitor of metalloproteinase-1 (TIMP-1) in renal mesangial (MG) cells, ultimately resulting in the deposition of collagen. However, the mechanism by which Hcys activates NADPH oxidase in these glomercular cells and whether this signaling pathway contributes to glomerular injury induced by hHcys in vivo remains unknown. Ceramide is a critical signaling molecule that mediates the activation of NADPH oxidase in different cells. NADPH oxidase contains the small G protein, Rac GTPase, which possesses a high affinity for lipid binding and plays an important role in the regulation of this enzyme. In the present study, we performed a series of in vitro and in vivo experiments to test the hypothesis that Hcys-induced ceramide production activates Rac-GTPase and thereby enhances NADPH oxidase activity and O2·- production in the cultured mesangial cells and the glomeruli of hyperhomocysteinemic rats, consequently resulting in glomerulosclerosis.; Thin Layer Chromatography (TLC) analysis demonstrated that L-Hcys increased de novo production of ceramide in rat MG cells. L-Hcys and increased ceramide did not alter the amount of NADPH oxidase subunit p47 phox and p67phox in both membrane and cytosolic fractions from MG cells. However, L-Hcys or ceramide markedly increased Rac GTPase activity, which was accompanied by enhanced activity of NADPH oxidase. These Hcys or ceramide-induced actions were substantially inhibited by the Rac GTPase inhibitor, GDPbetaS and the de novo ceramide synthesis inhibitor, fumonisin B1 (FB1 ). These results indicate that Hcys activates NADPH oxidase by stimulating de novo ceramide synthesis and consequent activation of Rac GTPase in rat MG cells.; To determine the role of Rac GTPase-NADPH oxidase activity in the mechanisms of Hcys-induced reduction of MMP-1 activity in these cells, RNA interference by small inhibitory RNA (siRNA) duplex was employed to reduce Rac expression and activity in rat MG cells. (Abstract shortened by UMI.)
机译：高同型半胱氨酸血症（hHcys）在晚期肾病（ESRD）的进展以及与ESRD相关的心血管并发症的发展中已成为一种关键的致病因素。我们实验室先前的研究表明，Hcys可通过NADPH氧化酶急剧增加超氧化物（O2·-）的产生，从而刺激肾小球系膜（MG）细胞中金属蛋白酶-1（TIMP-1）组织抑制剂的形成，最终导致在胶原蛋白的沉积。然而，Hcys激活这些肾小球细胞中NADPH氧化酶的机制以及该信号通路是否在体内由hHcys诱导的肾小球损伤尚不明确。神经酰胺是在不同细胞中介导NADPH氧化酶激活的关键信号分子。 NADPH氧化酶包含小的G蛋白Rac GTPase，它对脂质结合具有很高的亲和力，并且在调节该酶中起重要作用。在本研究中，我们进行了一系列体外和体内实验，以检验Hcys诱导的神经酰胺生成激活Rac-GTPase从而增强培养的系膜细胞和肾小球肾小球NADPH氧化酶活性和O2·-生成的假说。高同型半胱氨酸血症大鼠，因此导致肾小球硬化。薄层色谱（TLC）分析表明，L-Hcys可增加大鼠MG细胞中神经酰胺的重新产生。 L-Hcys和增加的神经酰胺不会改变MG细胞膜和胞质组分中NADPH氧化酶亚基p47 phox和p67phox的量。但是，L-Hcys或神经酰胺显着增加了Rac GTPase的活性，并伴随着NADPH氧化酶活性的增强。这些Hcys或神经酰胺诱导的作用被Rac GTPase抑制剂GDPbetaS和从头神经酰胺合成抑制剂fumonisin B1（FB1）基本上抑制。这些结果表明，Hcys通过刺激从头神经酰胺合成并因此激活了大鼠MG细胞中的Rac GTPase来活化NADPH氧化酶。为了确定Rac GTPase-NADPH氧化酶活性在这些细胞中Hcys诱导的MMP-1活性降低的机制中的作用，采用了小抑制性RNA（siRNA）双链体的RNA干扰来降低Rac在大鼠MG细胞中的表达和活性。 。 （摘要由UMI缩短。）

著录项

  • 作者

    Yi, Fan.;

  • 作者单位

    The Medical College of Wisconsin.;

  • 授予单位 The Medical College of Wisconsin.;
  • 学科 Health Sciences Pharmacology.; Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 179 p.
  • 总页数 179
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

  • 入库时间 2022-08-17 11:40:13

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