Mitochondrial Bioenergetics in the Kidney: Sex-specific Computational Modelling

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The renal tubules reabsorb >99% of the glomerular filtrate, in part via active transport processes that necessitate energy utilization. The transcellular concentration gradients that drive tubular transport are primarily established by Na+-K+-ATPase pumps that use ATP hydrolysis as a source of energy, which, in turn, requires a sustained rate of ATP generation, mostly by aerobic processes. The kidneys thus have the second highest O2 consumption rate after the heart. The greatest density of mitochondria is found in the proximal tubules and thick ascending limbs. Despite the great importance of renal metabolism and wide recognition of the role of cellular metabolism in other diseases, relatively few studies have focused on these aspects in the development of hypertension. Recent studies in humans and animal models, however, have stirred mounting interest in the role that alterations of renal substrate and energy metabolism may play in hypertension, although the molecular basis and relevance of these metabolic derangements remain largely unknown, and most studies have been primarily descriptive. To fill these knowledge gaps, international collaborators Cowley Jr and Dash are conducting experiments that will provide the needed data for a quantitative understanding of the cellular and molecular mechanisms underlying the development of oxidative stress and reduced efficiency of mitochondrial O2 utilization for ATP production in the kidney during the development of salt-sensitive hypertension. As the Canadian collaborator, Layton and her group will develop computational models that will provide a unique quantitative and mechanistic framework enabling testable predictions of the complex relationships existing between mitochondrial O2 utilization, energy production, and oxidative stress in the kidney during the development of salt-sensitive hypertension. Separate models will be developed for males and females, to study sex differences in these processes. Identification of new and sex-specific therapeutic targets could thereby emerge.