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

• 批准号: 10472035
• 负责人: Daria Ilatovskaya
• 金额: $ 52.54万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 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/10472035
• 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; Dahl Hypertensive Rats; 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; Hormones; Hydrogen Peroxide; 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; Superoxides; TAC1 gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Vasodilation; attenuation; base; 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

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.

项目总结