Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol 308: F1343-F1357, 2015. First published April 8, 2015 doi:10.1152/ajprenal.00007.2015.-The objective of this study was to investigate how physiological, pharmacological, and pathological conditions that alter sodium reabsorption (T Na) in the proximal tubule affect oxygen consumption (QO 2 ) and Na ϩ transport efficiency (TNa/QO 2 ). To do so, we expanded a mathematical model of solute transport in the proximal tubule of the rat kidney. The model represents compliant S1, S2, and S3 segments and accounts for their specific apical and basolateral transporters. Sodium is reabsorbed transcellularly, via apical Na ϩ /H ϩ exchangers (NHE) and Na ϩ -glucose (SGLT) cotransporters, and paracellularly. Our results suggest that TNa/QO 2 is 80% higher in S3 than in S1-S2 segments, due to the greater contribution of the passive paracellular pathway to TNa in the former segment. Inhibition of NHE or Na-K-ATPase reduced T Na and QO 2 , as well as Na ϩ transport efficiency. SGLT2 inhibition also reduced proximal tubular T Na but increased QO 2 ; these effects were relatively more pronounced in the S3 vs. the S1-S2 segments. Diabetes increased TNa and QO 2 and reduced TNa/QO 2 , owing mostly to hyperfiltration. Since SGLT2 inhibition lowers diabetic hyperfiltration, the net effect on TNa, QO 2 , and Na ϩ transport efficiency in the proximal tubule will largely depend on the individual extent to which glomerular filtration rate is lowered. sodium transport; glucose; metabolism; diabetes DESPITE INTENSE RESEARCH, the mechanisms underlying the development of chronic kidney diseases remain incompletely understood. Renal hypoxia is thought to be a unifying pathway to chronic kidney disease (15) and, in general, is due to a mismatch between changes in renal oxygen delivery and oxygen consumption (8). Oxygen consumption in the kidney serves in large part to actively reabsorb Na ϩ . Since the proximal tubule is where more than half the filtered load of Na ϩ is reabsorbed, the goal of this study was to investigate how physiological and pathological changes in sodium transport alter O 2 consumption in the proximal tubule.Sodium reabsorption along the proximal tubule is coupled to HCO 3 Ϫ and Cl Ϫ transport: early NaHCO 3 reabsorption raises the luminal concentration of Cl Ϫ and enhances the driving force for paracellular NaCl reabsorption in the later part of the tubule. Notably, changes in O 2 consumption (Q O 2 ) do not always correlate positively with changes in Na ϩ reabsorption. Deng et al. (4) observed that blocking carbonic anhydrase with benzolamide (a proximal tubule diuretic) lowered the energy efficiency of Na ϩ reabsorption in the kidney, as it simultaneously decreased net Na ϩ reabsorption and increased overall O 2 consumption. These effects were abolished by drugs that suppress Na ϩ /H ϩ exchange or basolateral Na ϩ -HCO 3 Ϫ cotransport. Deng et al. (4) surmised that benzolamide...