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

（请保持文字，不要PDF） 项目摘要/摘要 盐敏感性高血压和肾损伤的发生机制尚不完全清楚。众所周知，肾单位对滤过钠（Na+）的过度重吸收在盐敏感性高血压的发展中起主要作用，但近端小管（PT）病理对肾损害进展的影响尚不完全清楚。PT在依赖于由基底外侧Na，K-ATP酶活性产生的ATP依赖性电化学梯度的过程中重吸收约65%的过滤Na+。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肾小管Na+升高时，缺乏下调Na+转运蛋白PT表达和Na，K-ATP酶活性的能力。这导致高血压、肾小球损伤和血浆蛋白的超滤，这些血浆蛋白也使用ATP依赖性过程在PT处被重吸收。预计增加的Na，K-ATP酶活性将增加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PT病理学。在SS模型中研究调节病理学进展的机制的一个基本挑战是，高盐饮食是观察到的病理学变化级联的核心。本研究的目的是分离下游Na+处理和肾脏病理的PT病理的Na+依赖性和Na+非依赖性原因。我们假设PT损伤对SS大鼠盐敏感性病理学的进展有重要贡献。本项目的目的只有一个，即确定PT顶端起泡是否增加SS大鼠相对于盐不敏感Sprague道利（SD）大鼠的近端后Na+重吸收、肾小管铸型、纤维化和高血压。我们检验这一假设的方法是诱导足细胞损伤，导致SS和SD大鼠的Na+和压力非依赖性超滤和随后的PT起泡。将评估近端和近端后肾单位Na+重吸收、肾功能、蛋白尿、血压、肾小管/肾脏病理学以及PT Na+转运蛋白在肾单位和排泄泡中的分布。拟定的研究具有重要意义，因为钠摄取增加导致SS大鼠中观察到的肾脏病理学进展的机制尚不清楚。这些研究的结果将为PT损伤对盐敏感性高血压的贡献提供新的见解。

(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.