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Gene transfer approach in studying rat models of hypertension and diabetic organ damage.

机译：基因转移方法在研究高血压和糖尿病器官损害的大鼠模型中。

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摘要

Tissue kallikrein is a serine proteinase that is known for its ability to process low molecular weight kininogen to release the vasoactive peptide hormone called kinin. Adrenomedullin (AM) is a 52-amino acid vasodilatory peptide. In order to examine the role of kallikrein/kinin and AM in volume-dependent hypertension, adenoviral vectors harboring either the kallikrein or AM gene were delivered to deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Kallikrein gene delivery delayed blood pressure increases for 3 weeks and achieved a maximum reduction of 50 mmHg. Kallikrein gene delivery also prevented renal damage as observed by a significant reduction in urinary protein levels and glomerular and tubular damage. AM gene delivery induced sustained blood pressure reduction, enhanced renal function and prevented renal damage. AM also protects against cardiac remodeling as evident by AM-mediated reduction in left ventricular weight, cardiomyocyte diameter and extracellular matrix formation. Significant increases in urinary and cardiac cAMP levels indicate activation of the target receptors. These findings show that kallikrein and AM protects against cardiovascular and renal damage in volume-overload hypertension, suggesting a possible therapeutic value in treatment of cardiovascular and renal diseases.; Diabetic cardiomyopathy ranges in severity from mild dysfunction to failure. AM gene transfer to STZ-diabetic rats showed significant improvements in cardiac function as observed by decreased left ventricle end diastolic pressure, increased cardiac output, cardiac index, heart rate and ±ΔP/Δt values. AM also reduced glycogen levels in both the heart and kidney, demonstrated by histological staining and chemical analysis. AM gene delivery resulted in reduction of renal tubular damage. Diabetic rats treated with AM also significantly gained body weight compared to STZ control rats. Increased cardiac cAMP levels along with increased cAMP and cGMP urinary levels occurred in rats receiving AM gene delivery. Western blot analysis revealed increased phosphorylated Akt in cardiac tissue and increased membrane-bound Glut4 levels in skeletal muscle of AM-treated STZ-diabetic rats. These data indicates that AM plays a role in protection of cardiac and renal dysfunction in hyperglycemic rats acting in part via cAMP and Akt-NO-cGMP signal transduction pathways.
机译：组织激肽释放酶是一种丝氨酸蛋白酶，以其处理低分子量激肽原以释放血管活性肽激素（称为激肽）的能力而闻名。肾上腺髓质素（AM）是52个氨基酸的血管舒张肽。为了检查激肽释放酶/激肽和AM在体积依赖性高血压中的作用，将携带激肽释放酶或AM基因的腺病毒载体递送至乙酸脱氧皮质酮（DOCA）-盐高血压大鼠。激肽释放酶基因的递送延迟了3周的血压升高，并最大降低了50 mmHg。如通过尿蛋白水平的显着降低以及肾小球和肾小管损害所观察到的，激肽释放酶基因的递送还预防了肾损害。 AM基因的递送可导致持续的血压降低，增强的肾功能并防止肾脏损害。 AM还可以防止心脏重塑，如AM介导的左心室重量减少，心肌细胞直径减少和细胞外基质形成所证明。尿液和心脏中cAMP水平的显着增加表明靶受体的激活。这些发现表明激肽释放酶和AM在容量超负荷的高血压中可预防心血管和肾脏损害，表明在心血管和肾脏疾病的治疗中可能具有治疗价值。糖尿病性心肌病的严重程度从轻度功能障碍到衰竭。通过降低左心室舒张压，增加心输出量，心指数，心率和±ΔP/Δt值可以看出，AM基因转移到STZ糖尿病大鼠中后，心脏功能显着改善。组织学染色和化学分析表明，AM还降低了心脏和肾脏的糖原水平。 AM基因的递送导致肾小管损伤的减少。与STZ对照大鼠相比，接受AM治疗的糖尿病大鼠的体重也显着增加。在接受AM基因递送的大鼠中，心脏cAMP水平升高，而cAMP和cGMP尿水平升高。 Western印迹分析显示，AM治疗的STZ糖尿病大鼠心脏组织中磷酸化的Akt增加，而骨骼肌膜结合的Glut4水平增加。这些数据表明，AM在部分通过cAMP和Akt-NO-cGMP信号转导途径起作用的高血糖大鼠中，在保护心脏和肾脏功能障碍中起作用。

著录项

  • 作者

    Dobrzynski, Eric Gene.;

  • 作者单位

    Medical University of South Carolina.;

  • 授予单位 Medical University of South Carolina.;
  • 学科 Biology Molecular.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 191 p.
  • 总页数 191
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;病理学;
  • 关键词

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