Reno-protection afforded by combinatory approach targeting AT2R and neprilysin in obesity

针对肥胖症中 AT2R 和脑啡肽酶的组合方法提供的 Reno 保护

• 批准号: 10019322
• 负责人: Elizabeth Gray
• 金额: $ 3.47万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2022-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019322
• 关键词: Accreditation; Agonist; Albumins; Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Atrial Natriuretic Factor; Attenuated; Binding; Biochemical; Biological; Blood Pressure; Blood Pressure Monitors; Cardiovascular Physiology; Cardiovascular system; Chronic; Clinical; Combined Modality Therapy; Creatinine; Data; Diabetes Mellitus; Diet; EFRAC; Enalapril; Female; Future; Glomerular Filtration Rate; Heart failure; Histologic; Hypertension; Impairment; In Vitro; Incubated; Individual; Injury; Injury to Kidney; Kidney; Knowledge; Laboratories; Liquid Chromatography; Mediating; Messenger RNA; Metabolism; Metalloproteases; Methods; Monitor; Natriuresis; Natriuretic Peptides; Neprilysin; Obesity; Obesity Related Hypertension; Outcome; Pathologic; Pathology; Peptide Metabolism; Peptide Receptor; Peptides; Peptidyl-Dipeptidase A; Periodic acid Schiff stain method; Pharmaceutical Preparations; Plasma; Prevalence; Process; Production; Proteins; Proteinuria; Public Health; Publishing; Rattus; Receptor, Angiotensin, Type 1; Renal function; Renin; Renin-Angiotensin System; Reporting; Research Project Grants; Risk; Risk Factors; Site; Sodium; Sodium Chloride; Stable Isotope Labeling; Stains; Structure; Suspensions; Telemetry; Testing; Therapeutic; Thinness; Type 2 Angiotensin II Receptor; Vasodilation; Work; Zucker Rats; comorbidity; hemodynamics; high salt diet; improved; inhibitor/antagonist; kidney cortex; kidney dysfunction; male; novel; novel strategies; novel therapeutics; obesity treatment; pre-doctoral; pressure; receptor; receptor expression; response; salt sensitive hypertension; sex; tandem mass spectrometry; treatment duration; urinary; valsartan

Abstract The increasing world-wide prevalence of obesity is a worrying public health problem and crisis. Coexistence of obesity, hypertension and diabetes significantly increases the risk of kidney dysfunction. In obesity, concentrations of angiotensin II (Ang II) increase, while those of Ang-(1-7) decrease along with activity of angiotensin converting enzyme 2 (ACE2). Neprilysin (NEP) and ACE2 are metallopeptidases that process Ang I and Ang II, respectively into the Mas receptor agonist, Ang-(1-7). The activity of these protective renin angiotensin system (RAS) components counterbalances the detrimental biological effects of the classical Ang II/angiotensin II type 1 receptor (AT1R) RAS axis. Recently published and preliminary data from our laboratory suggests that treatment with AT2R agonist compound 21 (C21) decreases Ang II and increases Ang-(1-7) in the kidney of obese Zucker rats, by increasing expression and activity of ACE2. Furthermore, our in vitro data suggests that AT2R agonist treatment decreases renin activity as well. Entresto, a dual AT1R blocker (valsartan) and neprilysin inhibitor (sacubitril) recently released to the market was found to be superior to enalapril therapy alone in the PARADIGM HF trial, resulting in its indication for heart failure with reduced ejection fraction. The benefits of Entresto are accredited to its ability to increase concentrations of atrial natriuretic peptide (ANP), another substrate of NEP, while blocking the increasing concentrations of Ang II from acting on AT1R. Yet, Entresto was found to cause an increase in the urinary albumin/creatinine ratio, an indicator of kidney injury. This knowledge along with our preliminary results led to our hypothesis that Ang-(1-7) level in obese kidney is decreased by NEP inhibition, with concurrent increase in Ang II. Combination therapy with C21 increases Ang- (1-7) and attenuates Ang II, by increasing ACE2 activity and expression. Moreover, C21 with NEP inhibition produces an additive effect on increasing ANP levels in obese kidney protecting function and structural integrity of the kidney. To test this hypothesis, Aim 1 is directed to determine the basal levels and basic metabolism of Ang peptides and ANP in obese kidney. Aim 2 will determine that combined treatment (short-term) with NEP inhibitor and AT2R agonist enhances ACE2 activity and Ang-(1-7) levels, and attenuates Ang II levels and ANP degradation in obesity. Aim 3 will determine that chronic combination therapy with a NEP inhibitor and AT2R agonist is reno-protective in salt-induced hypertension in obesity and is superior to Entresto (ARB + NEP inhibitor). Female obese Zucker rats are included in aim 3 to investigate the sex specific outcomes of our novel combinatory approach and to determine if it is equally effective in both male and female obese Zucker rats. To accomplish these aims, Ang peptides will be quantified utilizing our new liquid chromatography tandem mass spectrometry method; biochemical, histological and hemodynamic approaches to study renal function/injury and telemetry for monitoring blood pressure. The proposed work will significantly contribute to understanding Ang metabolism in obesity and impact future clinical perspectives for a novel reno-protective therapeutic approach.

抽象的 肥胖的全球流行率不断提高，这是一个令人担忧的公共卫生问题和危机。共存 肥胖，高血压和糖尿病可显着增加肾功能障碍的风险。在肥胖中， 血管紧张素II（ANG II）的浓度增加，而Ang-（1-7）的浓度随着活性而降低 血管紧张素转化酶2（ACE2）。 Neprilysin（NEP）和ACE2是加工ANG的金属肽酶 I和Ang II分别进入MAS受体激动剂，Ang-（1-7）。这些受保护的肾素的活性 血管紧张素系统（RAS）组件抵消经典ANG的有害生物学作用 II/血管紧张素II型1受体（AT1R）RAS轴。最近出版了我们实验室的初步数据 表明用AT2R激动剂化合物21（C21）治疗会降低ANG II并增加Ang-（1-7） 肥胖的扎克大鼠的肾脏，通过增加ACE2的表达和活性。此外，我们的体外数据 表明AT2R激动剂治疗也会降低肾素活性。 Entresto，双重AT1R阻滞剂（Valsartan） 和Neprilysin抑制剂（Sacubitril）最近发布到市场相比 仅在范式HF试验中单独使用，导致其心力衰竭的指示，射血分数降低。这 Entresto的好处获得了增加心房脂肪胡椒（ANP）的能力的认可。 NEP的另一个底物，同时阻止了在AT1R上作用的ANG II浓度的增加。然而， 发现Entresto会导致尿白蛋白/肌酐比率增加，这是肾脏损伤的指标。 这些知识以及我们的初步结果导致了我们的假设，即肥胖肾中的ang-（1-7）水平是 通过NEP抑制减少，随着ANG II的同时增加。与C21的联合疗法增加了ang- （1-7）并通过增加ACE2活性和表达来减轻ANG II。此外，C21具有NEP抑制 对肥胖肾脏保护功能和结构完整性的ANP水平的提高产生额外的影响 肾脏。为了检验这一假设，AIM 1被指示确定基本水平和基本代谢 肥胖肾脏中的Ang肽和ANP。 AIM 2将确定与NEP合并治疗（短期） 抑制剂和AT2R激动剂增强ACE2活性和ANG-（1-7）水平，并减轻ANG II水平和ANP 肥胖症的降解。 AIM 3将确定使用NEP抑制剂和AT2R的慢性组合疗法 激动剂在肥胖症中盐诱导的高血压方面具有肾脏保护性，并且优于Entresto（ARB + NEP 抑制剂）。 AIM 3中包括雌性肥胖的扎克大鼠，以研究我们小说的性别特定结果 结合性方法并确定在男性和女性肥胖扎克大鼠中是否同样有效。到 完成这些目的，将使用我们的新液相色谱量量量化ANG肽 光谱法；研究肾功能/损伤的生化，组织学和血液动力学方法 用于监测血压的遥测。拟议的工作将有助于理解ANG 肥胖症中的代谢并影响了一种新型的肾脏保护治疗方法的未来临床观点。