Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

摘要

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 (Q_(O_2)) and Na~+ transport efficiency (T_(Na)/Qo,). 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~+/H~+ exchangers (NHE) and Na~+-glucose (SGLT) cotransporters, and paracellularly. Our results suggest that T_(Na)/Q_(O_2) is 80% higher in S3 than in S1-S2 segments, due to the greater contribution of the passive paracellular pathway to T_(Na) in the former segment. Inhibition of NHE or Na-K-ATPase reduced T_(Na) and Q_(O_2), as well as Na~+ transport efficiency. SGLT2 inhibition also reduced proximal tubular T_(Na) but increased Q_(O_2); these effects were relatively more pronounced in the S3 vs. the S1-S2 segments. Diabetes increased T_(Na) and Q_(O_2) and reduced T_(Na)/Q_(O_2), owing mostly to hyperfiltration. Since SGLT2 inhibition lowers diabetic hyperfiltra-tion, the net effect on T_(Na), Q_(O_2), and Na~+ transport efficiency in the proximal tubule will largely depend on the individual extent to which glomerular filtration rate is lowered.