High Salt Remodels Renal Cortical and Proximal Tubular Metabolism: Metabolic Fuels, Oxidative Stress, and Hypertension

Medical College Of Wisconsin, Milwaukee WI

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Excessive dietary salt has detrimental effects on cardiovascular and kidney health, leading to hypertension and chronic kidney disease. Salt-sensitivity, prevalent in nearly half of the US hypertension population and more common in African American and Asian populations, triples the risk of chronic kidney disease and double the incidence of cardiovascular events. Little is known about the effects of a high salt diets upon kidney intermediate metabolism. We hypothesize that changes in kidney metabolism contribute to these events, particularly in salt- sensitive individuals or inbred salt-sensitive rats. We have recently found that the renal cortex undergoes remarkable changes in the metabolic landscape in normal salt-resistant rats (e.g., Sprague Dawley) when rats are fed a high salt diet. It was unexpectedly found that crucial metabolic pathways for energy production, notably the TCA cycle, were downregulated while genes and enzymes involved in glycolysis were upregulated. This remarkable switch toward aerobic glycolysis appears to be a protective mechanism that we propose may not occur in salt-sensitive rats yielding injurious consequences. Based on our preliminary studies, we propose that in salt-sensitive rats, a high salt diet initially enhances metabolic pathways involved in sodium reabsorption, such as the TCA cycle and mitochondrial electron transport chain, resulting in increased oxygen consumption and ATP production. However, this leads to excess oxidative stress, an inability to compensate via aerobic glycolysis leading to tubular injury and decreased kidney function. We propose that by reducing mitochondrial oxidative stress in salt-sensitive rats using genetically derived rat models, metabolic pathways will be able to compensate, and supply the needed energy for sodium reabsorption. Our study compares the bioenergetic, transcriptomic, and metabolomic profiles of salt-sensitive rats to genetically engineered salt-resistant rats. Computer models will also aid in analyzing the complex metabolic alterations and testing mechanistic hypotheses. Overall, our goal is to understand how high salt diets affect kidney intermediary metabolism and identify targets to reduce kidney injury and blood pressure salt-sensitivity. The proposed work will be carried out through three Specific Aims. Aim 1 investigates mitochondrial respiration and ATP production in renal cortical proximal tubules, predicting that salt-sensitive rats will fail to sustain these processes due to rising oxidative stress. Aim 2 examines the failure of salt-sensitive rats to upregulate protective metabolic pathways, leading to kidney injury, compared to salt-resistant rats. Aim 3 develops mechanistic computational models to predict oxidative stress and metabolic changes in the kidneys of salt-sensitive rats compared to salt-resistant rats in response to increased metabolic workload imposed by increased sodium delivery to the proximal tubules during the development of hypertension and to identify potential therapeutic targets for reducing salt-sensitivity.