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

• 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
• 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

(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.

(请保存在Word中，不要保存为PDF) 项目摘要/摘要： 盐敏感型高血压和肾损伤的发病机制尚不完全清楚。已知肾单位对滤过钠(Na+)的过度重吸收在盐敏感型高血压的发生发展中起主要作用，但近端小管(PT)病理对肾损害进展的影响尚不完全清楚。PT在一个依赖于ATP依赖的电化学梯度的过程中重新吸收大约65%的过滤的Na+，该梯度是由基侧Na，K-ATPase活性产生的。与耐盐大鼠模型不同，Dahl盐敏感(SS)大鼠模型在长期高盐饮食导致高Na+时，缺乏下调Na+转运体PT表达和Na，K-ATPase活性的能力。这会导致高血压、肾小球损伤和血浆蛋白的超滤，这些蛋白也会通过依赖于ATP的过程在PT重新吸收。增强的Na，K-ATPase活性有望增加PT细胞的代谢和氧化应激，以满足增加的能量需求，最终导致观察到的PT病理。在SS模型中研究病理进展的调控机制的一个基本挑战是，高盐饮食是观察到的一连串病理变化的中心。这项研究的目的是从下游Na+处理和肾脏病理分离PT病理的Na+依赖和非Na+原因。我们假设PT损伤在SS大鼠盐敏感性病理的进展中起重要作用。该项目只有一个目的，就是确定与盐不敏感的SpragueDawley(SD)大鼠相比，PT根尖充血是否能增加SS大鼠近端Na+重吸收、肾小管铸型、纤维化和高血压。我们验证这一假说的方法是诱导足细胞损伤，导致SS和SD大鼠的钠离子和压力非依赖性高滤过以及随后的PT起泡。将评估近端和近端肾单位Na+重吸收、肾功能、蛋白尿、血压、肾小管/肾脏病理以及PT Na+转运蛋白在肾单位和排泄小泡中的分布。建议的研究具有重要意义，因为钠摄取增加导致SS大鼠肾脏病理进展的机制尚不清楚。这些研究结果将为PT损伤在盐敏感型高血压中的作用提供新的见解。