Effect of High Salt Diet on Proximal Tubular Sodium Reabsorption, Metabolic Stress, and Injury

高盐饮食对近端肾小管钠重吸收、代谢应激和损伤的影响

基本信息

批准号：
10908784
负责人：
Alison J Kriegel
金额：
$ 10万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-08 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10908784
关键词：
ATP phosphohydrolase Acute Acute Renal Failure with Renal Papillary Necrosis Aftercare Animals Apical Biological Markers Biological Process Blood Blood Pressure Body Weight Brush Border Bulla Carrier Proteins Chlorides Chromosome 13 Circulation Citric Acid Cycle Control Animal Creatinine clearance measurement Dahl Hypertensive Rats Development Diet Disease Dopamine Down-Regulation Endothelium Enzymes Equilibrium Excretory function Exhibits Fatty Acids Female Fibrosis Gene Chips Gene Expression Genomics Goals Health Homeostasis Human Hydroxyeicosatetraenoic Acids Hypertension Impairment Inbred Dahl Rats Inbreeding Individual Injury Injury to Kidney Intake Journals K ATPase Kidney Limb structure Lipids Measures Medicine Membrane Metabolic Metabolic stress Metabolism Mitochondria Modeling Molecular Na(+)-K(+)-Exchanging ATPase Natriuresis Nephrons Nephrotic Syndrome New England Norway Oxidative Stress Oxygen PPAR alpha Pathologic Pathology Perfusion Physiological Plasma Proteins Play Population Process Production Protein Array Proteins Proteinuria Proteomics Protocols documentation Protons Proximal Kidney Tubules Puromycin Aminonucleoside Rattus Reactive Oxygen Species Regulation Renal Blood Flow Renal function Renin Resistance Role Signal Transduction Sodium Sodium Chloride Sodium-Hydrogen Antiporter Sprague-Dawley Rats Testing Thick Time Tubular formation absorption apical membrane blood pressure elevation cell injury consomic dietary salt feeding glomerular filtration hemodynamics high salt diet hypertensive insight ischemic cardiomyopathy male mitochondrial dysfunction mouse model novel oxidation podocyte pressure prevent renal damage resistant strain response salt intake salt sensitive salt sensitive hypertension uptake urinary

项目摘要

(PLEASE KEEP IN WORD, DO NOT PDF) PROJECT Summary/ABSTRACT The mechanisms responsible for the development of salt-sensitive hypertension and renal injury are incompletely understood. It is known that excessive reabsorption of filtered sodium (Na+) by the nephron plays a primary role in the development in salt-sensitive hypertension, but the impact of proximal tubule (PT) pathology on the progression of renal damage is incompletely understood. The PT reabsorbs approximately 65% of filtered Na+ in a process that relies upon an ATP-dependent electrochemical gradient produced by basolateral Na,K-ATPase activity. Unlike salt-resistant rat models, the Dahl salt-sensitive (SS) rat model lacks the ability to downregulate PT expression of Na+ transporters and Na,K-ATPase activity when presented with high tubular Na+ resulting from a prolonged high salt diet. This results in hypertension, glomerular damage, and hyperfiltration of plasma proteins that are also reabsorbed at the PT using ATP-dependent processes. Augmented Na,K-ATPase activity would be expected to increase PT cellular metabolic and oxidative stress to meet the augmented energetic demand, ultimately resulting in observed PT pathology. A fundamental challenge with studying mechanisms regulating the progression of pathology in the SS model is that a high salt diet is central to the cascade of pathological changes observed. The goal of this study is to isolate Na+-dependent and Na+-independent causes of PT pathology on downstream Na+ handling and renal pathology. We hypothesize that PT damage importantly contributes to the progression of salt-sensitive pathology in the SS rat. This project has a single aim, to determine if PT apical blebbing augments postproximal Na+ reabsorption, tubular casting, fibrosis, and hypertension in the SS rat relative to salt-insensitive Sprague Dawley (SD) rats. Our approach to test this hypothesis will be to induce podocyte damage to cause Na+- and pressure-independent hyperfiltration and subsequent PT blebbing in SS and SD rats. Proximal and post-proximal nephron Na+ reabsorption, renal function, proteinuria, blood pressure, tubular/renal pathology, and distribution of PT Na+ transport proteins in the nephron and excreted blebs will be assessed. The proposed studies are significant because the mechanism by which enhanced sodium uptake leads to the progression of observed renal pathology in SS rats remains unclear. The results of these studies will provide novel insight into the contribution of PT damage to salt-sensitive hypertension.

（请以 WORD 形式保存，请勿以 PDF 形式保存）项目总结/摘要盐敏感性高血压和肾损伤的发生机制尚不完全清楚，已知肾单位对滤过的钠 (Na+) 的过度重吸收在盐敏感性高血压的发生中起主要作用，但盐敏感性高血压的影响。近端肾小管 (PT) 病理学对肾损伤进展的影响尚不完全清楚。近端肾小管 (PT) 重吸收约 65% 的滤过 Na+，这一过程依赖于基底外侧产生的 ATP 依赖性电化学梯度。与缺乏耐盐性的大鼠模型不同，Dahl 盐敏感 (SS) 大鼠模型能够下调 Na+ 转运蛋白的 PT 表达和 Na+，K-ATP 酶活性。长期高盐饮食会导致高血压、肾小球损伤和血浆蛋白的过度滤过，而血浆蛋白也会通过 ATP 依赖性过程而被重吸收。预计会增加 PT 细胞代谢和氧化应激以满足增加的能量需求，最终导致观察到的 SS 模型中病理进展调节机制的一个基本挑战是高盐饮食是级联反应的核心。本研究的目的是分离 Na+ 依赖性和 Na+ 非依赖性 PT 病理学对下游 Na+ 处理和肾脏病理学的影响。。这该项目有一个单一的目标，即确定相对于盐不敏感的 Sprague Dawley (SD) 大鼠，PT 心尖起泡是否会增强 SS 大鼠的近端 Na+ 重吸收、肾小管铸型、纤维化和高血压。足细胞损伤导致 SS 和 SD 大鼠近端和近端肾单位 Na+ 发生 Na+- 和压力非依赖性超滤以及随后的 PT 起泡。将评估重吸收、肾功能、蛋白尿、血压、肾小管/肾脏病理学以及肾单位和排泄泡中 PT Na+ 转运蛋白的分布，因为钠摄取增加导致肾病进展的机制很重要。在 SS 大鼠中观察到的肾脏病理学仍不清楚，这些研究的结果将为 PT 损伤对盐敏感性高血压的影响提供新的见解。