...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide
【24h】

Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide

机译：基于B型利钠肽选择性剪接的肾脏保护肽的生物设计

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics. We identified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intron-retained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax pre-constricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.
机译：可选的RNA剪接可能提供独特的机会来鉴定药物靶标和治疗药物。我们确定了由内含子保留导致的B型利钠肽（BNP）的替代剪接转录本。此成绩单出现在衰竭的人心中，并在机械卸载后减少。内含子保留的转录物将产生独特的34个氨基酸（aa）羧基末端，同时保持天然BNP的其余结构。我们针对此羧基末端产生了抗血清，并在衰竭的人类心脏组织中发现了免疫反应性。合成了选择性剪接的肽（ASBNP），与BNP不同，它未能刺激血管细胞或血管收缩前的动脉环中的cGMP。这表明ASBNP可能缺乏重组BNP的剂量限制作用。考虑到结构上的考虑，生成了ASBNP的羧基末端截短形式（ASBNP.1），并确定其保留了BNP刺激犬肾小球分离物和培养的人肾小球系膜细胞中cGMP的能力，但在血管细胞中缺乏类似的作用。在心力衰竭的起搏模式中，系统性输注ASBNP.1不会改变平均动脉压，但会增加肾小球滤过率（GFR），抑制血浆肾素和血管紧张素，同时引起利尿和利尿。与其独特的体内效应相一致，ASBNP.1的活性可能无法通过NPR-A或NPR-B的结合和激活来解释。因此，生物设计肽ASBNP.1增强了与心力衰竭相关的GFR，同时缺乏BNP的血管活性。这些发现表明，可以基于交替剪接的产物来设计具有独特性质的肽。

著录项

  • 来源
  • 作者

    Shuchong Pan; Horng H. Chen; Deborah M. Dickey; Guido Boerrigter; Candace Lee; Laurel S. Kleppe; Jennifer L. Hall; Amir Lerman; Margaret M. Redfield; Lincoln R. Potter; John C. Burnett Jr; Robert D. Simari;

  • 作者单位

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Division of Cardiology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

    Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    vasoactive; myocardial; kidney;

    机译：血管活性心肌肾;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号