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

Medical College Of Wisconsin, Milwaukee WI

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Abstract

(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.