REGULATION OF RENAL VASCULAR CELLS IN HYPERTENSION

高血压肾血管细胞的调节

• 批准号: 6389356
• 负责人: CRAIG H GELBAND
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2002-04-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389356
• 关键词: antisense nucleic acid; calcium channel; confocal scanning microscopy; gene therapy; glomerular filtration rate; hormone regulation /control mechanism; kidney circulation; kidney pharmacology; membrane channels; membrane potentials; potassium channel; protein kinase C; renal hypertension; renin angiotensin system; sarcoplasmic reticulum; single cell analysis; spontaneous hypertensive rat; vascular resistance; vascular smooth muscle; vasomotion; vasospasm; voltage /patch clamp

DESCRIPTION (Verbatim from Applicant's abstract): The relationship between renal blood flow and glomerular filtration rate is well established. A decrease in renal blood flow lowers glomerular filtration rate, triggering water retention and increases in extracellular fluid volume, cardiac output and arterial pressure. If both renal blood flow and glomerular filtration rate remain suppressed, the initial steps in the development of hypertension have taken place. Since changes in renal blood flow have been implicated in certain vascular disorders, including hypertension and renal vasospasm, this research will help fill the existing gap of knowledge regarding the relationship between ion channel regulation and vascular reactivity in the renal vasculature. It has been clearly shown that Kv, KCa and L-type Ca2+ channel activity in small resistance arterioles of the kidney are altered in the spontaneously hypertensive rat (SHR) and deoxycorticosterone acetate (DOCA) hypertensive rat when compared to their proper control. Yet the mechanism(s) by which these alterations take place has yet to be elucidate. The general hypothesis of this application is that regulation of K+ and Ca2+ channel activity, either by signaling molecules or by a change in number, depolarize membrane potential in renal resistance arteriolar vascular smooth muscle cells from hypertensive rats thereby increasing vascular smooth muscle tone. Using a multifaceted approach of vascular reactivity, patch clamp electrophysiology, molecular techniques (Western blot and RNase protection) and confocal microscopy, this research project will advance our understanding of the involvement of membrane conductances in the regulation of renal vascular excitation-contraction coupling and blood pressure in health and disease. The aims of the proposed research are fourfold: (1) To biophysically and pharmacologically characterize the mechanism(s) by which there is a decrease in Kv channel current density in renal resistance arteriolar vascular smooth muscle cells of hypertensive rat models. (2) To biophysically and pharmacologically characterize the mechanism(s) by which there is an increase in L-type Ca2+ channel current density in renal resistance arteriolar vascular smooth muscle cells from hypertensive rat models. (3) To characterize the relationship between Ca2+ release from the sarcoplasmic reticulum, PKC and the depressed activity of KCa channels in renal resistance arterioles and renal vascular smooth muscle cells from hypertensive rat models. (4) To examine if lowering blood pressure with antisense gene therapy targeting the rennin-angiotensin system can prevent/reverse the mechanism(s) that lead to alterations in Kv, KCa, and L-type Ca2+ channel activity. The results from these studies should significantly increase our knowledge of the mechanism(s) of hormonal modulation of vascular tone in a clinically relevant tissue, the renal vascular bed and its role in the development of hypertension.

描述（逐字病申请人的摘要）： 肾脏血流和肾小球滤过率已经很好地确定。减少 在肾脏血流中，降低肾小球滤过率，触发水 保留率并增加细胞外液体体积，心输出量和 动脉压。如果肾脏血流和肾小球滤过率 保持抑制，高血压发展的初始步骤 发生。由于肾脏血流的变化已与某些 这项研究 将有助于填补有关有关关系的现有知识差距 离子通道调节和肾血管中的血管反应性。它有 清楚地表明，小型KV，KCA和L型Ca2+通道活性 肾脏的抗性小动脉自发改变 高血压大鼠（SHR）和乙酸乙酸酯（DOCA）高血压大鼠 与他们的适当控制相比。然而，这些机制是这些机制 发生变化尚未阐明。一般假设 应用是对K+和Ca2+通道活动的调节 信号分子或通过数量变化，将膜电势去极化 高血压大鼠的肾抗性小动脉血管平滑肌细胞 从而增加血管平滑肌张力。使用多方面的方法 血管反应性，斑块夹电生理学，分子技术 （Western印迹和RNase保护）和共聚焦显微镜，这项研究 项目将促进我们对膜参与的理解 调节肾血管激发反应的电导 健康和疾病中的耦合和血压。提议的目的 研究是四重：（1）生物物理和药理表征的特征 KV通道电流密度降低的机制 高血压大鼠的肾脏电阻小动脉血管平滑肌细胞 型号。 （2）从生物物理和药理上表征 L型Ca2+通道电流增加的机制 肾阻力的密度小动脉血管平滑肌细胞 高血压大鼠模型。 （3）表征Ca2+之间的关系 从肌质网，PKC和KCA的抑郁活性中释放 肾脏阻力小动脉和肾血管平滑肌细胞中的通道 来自高血压大鼠模型。 （4）检查是否降低血压 靶向肾上腺素 - 血管紧张素系统的反义基因疗法可以 防止/逆转导致KV，KCA和KCA改变的机制 L型Ca2+通道活性。这些研究的结果应该 大大提高了我们对荷尔蒙调制机制的了解 在临床相关组织，肾脏血管床和 它在高血压发展中的作用。