Mitochondria-Mediated Effects and Therapeutic Potential of Atrial Natriuretic Peptide in Salt-Sensitive Hypertension Diversity Supplement

项目总结 目前尚无针对血压盐敏感型患者的特效药。 不幸的是，盐敏感性的分子机制仍然知之甚少。其中一个 盐敏感型(SS)高血压的主要发病机制涉及 肾脏排盐的能力。心钠素(ANP)是由NPPA编码的一种激素。 促进排盐降血压。有临床数据表明心钠素水平先天偏低 SS高血压的发生发展。在其他影响中，已知ANP(通过cGMP相关机制)是 有利于线粒体生物能量学和生物发生。然而，关于这方面的知识存在差距。 心钠素对肾脏线粒体的影响，特别是对SS高血压的影响。我们最重要的假设是 父母的计划是，在SS高血压中，ANP缺乏/对ANP的敏感性降低是导致肾脏的原因 线粒体功能障碍和相关的钠转运失衡。为了解决这一中心假设 在家长提案中，我们制定了三个具体目标：目标1.确定增加ANP水平是否有益 用于SS高血压患者的肾盐处理和心功能。目的2.确定低水平的肾脏cGMP是否 由于缺乏ANP，导致肾脏线粒体钙离子和活性氧物种(ROS)增加。 目的3.验证功能障碍导致钙离子平衡紊乱和ROS过度产生的假说 线粒体影响SS高血压患者的肾脏钠转运。从这些拟议的目标来看，斯皮尔斯博士和斯皮尔斯博士。 伊拉托夫斯卡娅提出的其他目标侧重于研究心钠素在SS高血压中的作用 肾小球功能和损伤的特异性。关于这一补充项目的重点，目标如下： 补编目的1.探讨心钠素对SS大鼠肾小球功能和损伤的生理影响 高血压。补编目的2.分析NPPA基因敲除对足细胞钙离子转运和细胞周期的影响。 SS高血压患者的线粒体功能。斯皮尔斯博士和伊拉托夫斯卡娅博士组成了一个非常强大的团队 帮助完成这些目标的导师和合作者，以及斯皮尔斯博士在 该副刊将与严格的职业发展计划相结合。圆满完成 父提案中的拟议研究以及本补充奖励的拟议研究将 解开盐敏感的新的因果机制。

PROJECT SUMMARY There is no specific treatment available for the subpopulation of patients with salt sensitivity of blood pressure (BP); unfortunately, the molecular mechanisms underlying salt-sensitivity remain poorly understood. One of the major proposed mechanisms for the development of salt-sensitive (SS) hypertension involves a defect in the ability of the kidneys to excrete salt. Atrial Natriuretic Peptide (ANP) encoded by Nppa, is a hormone known to promote salt excretion and BP reduction. There are clinical data implicating inherently low levels of ANP in the development of SS hypertension. Among other effects, ANP (via cGMP-related mechanisms) is known to be beneficial for mitochondrial bioenergetics and biogenesis. However, there is a gap in knowledge regarding the effects of ANP on mitochondria in the kidney, especially in SS hypertension. Our overarching hypothesis of the parent project is that in SS hypertension ANP deficiency/reduced sensitivity to ANP is causative to renal mitochondrial dysfunction and associated sodium transport imbalance. To address the central hypothesis of the parent proposal, we developed three specific aims: Aim 1. Establish whether increased ANP levels are beneficial for renal salt handling and cardiac function in SS hypertension. Aim 2. Determine whether low renal cGMP level resulting from lack of ANP causes an increase in renal mitochondrial Ca2+ and reactive oxygen species (ROS). Aim 3. Test the hypothesis that disrupted Ca2+ balance and excessive ROS production by dysfunctional mitochondria affect renal sodium handling in SS hypertension. From these proposed aims Dr. Spires and Dr. Ilatovskaya derived additional aims focused on studying the effects of ANP in SS hypertension in the context of glomerular function and injury specifically. For the focus of this supplemental project the aims are as follows: Suppl. Aim 1. To determine the physiological effects of ANP on glomerular function and injury in SS hypertension. Suppl. Aim 2. To analyze the effects of Nppa knockout on podocyte calcium handling and mitochondrial function in SS hypertension. Dr. Spires and Dr. Ilatovskaya put together a very strong team of mentors and collaborators to aid in completion of these Aims, and the methodological training of Dr. Spires during the Supplement will be combined with a rigorous career development program. The successful completion of the proposed studies in the parent proposal as well as the those proposed for this supplemental award will unravel the novel cause-effect mechanisms of salt-sensitivity.