Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension

心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力

基本信息

批准号：
10676800
负责人：
Daria Ilatovskaya
金额：
$ 52.54万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-14 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676800
关键词：
Acute Address Adipose tissue Affect Animal Model Animals Antioxidants Atrial Natriuretic Factor Attenuated Bioenergetics Biogenesis Blood Pressure Blood Pressure Monitors Cells Chronic Clinic Clinical Data Cultured Cells Cyclic GMP Data Defect Development Disease Diuresis Duct (organ) structure Echocardiography Electrophysiology (science)Energy Metabolism Equilibrium Event Excretory function Exhibits Experimental Designs Free Radical Formation Functional disorder Generations Heart failure Heterozygote Hormones Hydrogen Peroxide Hypertension Image Impairment Individual Infusion procedures Injury to Kidney Kidney Knock-out Knowledge Link Location Measurement Mediating Metabolic Microscopy Mitochondria Molecular Molecular Biology Muscle Natriuretic Peptides Nephrons Organ Pathologic Pathway interactions Peptide Signal Sequences Permeability Persons Pharmaceutical Preparations Phenotype Pilot Projects Plasma Production Rattus Reactive Oxygen Species Regulation Renal Blood Flow Renal Tissue Resistance Respiration Sodium Sodium Chloride Spin Trapping Spirometry Superoxides TAC1 gene Techniques Testing Therapeutic Therapeutic Effect Tissues Vasodilation absorption attenuation blood flow measurement blood pressure control blood pressure elevation blood pressure reduction cGMP production design dietary salt effective therapy epithelial Na+ channel heart function high risk hypertension treatment hypertensive improved in vivo metabolic abnormality assessment mitochondrial dysfunction novel patch clamp patient subsets receptor sensitivity recruit renal damage salt intake salt sensitive salt sensitive hypertension treatment strategy

项目摘要

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, and 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 pilot studies demonstrated that during a high salt challenge Nppa-/- (ANP knockout) Dahl SS rats exhibit exacerbated salt-sensitivity, reduced sodium excretion, and aggravated kidney injury, which is associated with mitochondrial damage and dysfunction. We also showed that there is dysregulation of renal sodium transporters, in the Nppa-/- rats compared to wild-type controls, and the activity of the Epithelial Na+ Channel (ENaC) is elevated in the collecting ducts. Chronic ANP infusion in wild-type SS rats resulted in a dramatic attenuation of salt-induced BP increase and alleviated organ damage. We hypothesize 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 this project, 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. We generated abundant evidence to support these aims, created a rigorous and comprehensive experimental design and established novel cutting-edge techniques to address the hypothesis. We recruited strong collaborative expertise, and will implement a combination of whole-animal studies and in vivo techniques (blood pressure monitoring with drug infusion, metabolic studies and GFR measurements), electrophysiology (single channel and whole-cell patch-clamp of the freshly isolated nephrons and isolated mitochondria), advanced microscopy, mitochondrial spectrofluorimetry and respirometry, and routine molecular biology approaches. The successful completion of the proposed studies will unravel the novel causative mechanisms of salt-sensitivity.

项目摘要没有针对血压盐敏感性的患者亚群的特定治疗方法（bp）;不幸的是，盐敏感性基础的分子机制仍然了解不足。中的一个盐敏感（SS）高血压开发的主要提出的机制涉及缺陷肾脏排泄盐的能力。由NPPA编码的心房亚钠肽（ANP）是已知的激素促进盐分排泄和降低BP，并且有临床数据暗示固有的ANP固有水平 SS高血压的发展。除其他效果外，已知ANP（通过CGMP相关机制）是有益于线粒体生物能和生物发生。但是，关于 ANP对肾脏线粒体的影响，尤其是在SS高血压下。我们的试点研究表明在高盐挑战期间减少钠排泄和严重的肾脏损伤，这与线粒体损伤和功能障碍。我们还表明，在NPPA - / - 大鼠中存在肾脏钠转运蛋白的失调与野生型对照相比，在收集中升高上皮Na+通道（ENAC）的活性管道。野生型SS大鼠的慢性ANP输注导致盐引起的BP的衰减显着衰减并减轻器官损坏。我们假设在SS高血压ANP缺乏/降低对ANP的敏感性是肾脏的原因线粒体功能障碍和相关的钠转运失衡。解决此的中心假设项目，我们开发了三个具体目标：目标1。确定增加的ANP水平是否有益 SS高血压中的肾脏盐处理和心脏功能。 AIM 2。确定低肾脏CGMP水平是否由于缺乏ANP，导致肾脏线粒体Ca2+和活性氧（ROS）的增加。目标3。检验以下假设，即破坏了CA2+平衡和功能失调的ROS产生过多的假设线粒体会影响SS高血压中的肾脏钠处理。我们产生了丰富的证据来支持这些目标，创造了严格而全面的实验设计并建立了新的尖端技术来解决该假设。我们招募了强者协作专业知识，并将实施整个动物研究和体内技术的结合（血液用药物输注，代谢研究和GFR测量的压力监测），电生理学（单个新鲜分离的肾单位和孤立的线粒体的通道和全细胞斑块钳），晚期显微镜，线粒体光谱法和呼吸测定法以及常规的分子生物学方法。这成功完成拟议的研究将揭示盐敏感性的新型致病机制。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional role of histamine receptors in the renal cortical collecting duct cells.

DOI：
10.1152/ajpcell.00420.2021
发表时间：
2022-01
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
A. Sudarikova;Mikhail V Fomin;Regina F. Sultanova;Ying Zhao;Samantha Perez;Mark Domondon;Margarita Shamatova;Daria V Lysikova;Denisha R. Spires;D. Ilatovskaya
通讯作者：
A. Sudarikova;Mikhail V Fomin;Regina F. Sultanova;Ying Zhao;Samantha Perez;Mark Domondon;Margarita Shamatova;Daria V Lysikova;Denisha R. Spires;D. Ilatovskaya

Editorial: Role of Molecular Modulators in Combatting Cardiac Injury and Disease: Prevention, Repair and Regeneration.

DOI：
10.3389/fcvm.2022.861442
发表时间：
2022
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
通讯作者：

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.

DOI：
10.14814/phy2.15652
发表时间：
2023-04
期刊：
Physiological reports
影响因子：
2.5
作者：
通讯作者：

Innate-like T-cells correlate with functional changes post-myocardial infarction.

先天样 T 细胞与心肌梗塞后的功能变化相关。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Corker,Alexa;Broughton,Philip;Troncoso,Miguel;Deleon-Pennell,KristineY
通讯作者：
Deleon-Pennell,KristineY

Epithelial Sodium Channel Alpha Subunit (αENaC) Is Associated with Inverse Salt Sensitivity of Blood Pressure.

DOI：
10.3390/biomedicines10050981
发表时间：
2022-04-23
期刊：
Biomedicines
影响因子：
4.7
作者：
Xu P;Sudarikova AV;Ilatovskaya DV;Gildea JJ;Akhter M;Carey RM;Yue W;Jose PA;Felder RA
通讯作者：
Felder RA