title: Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition.
abstract: The objective of this study was to investigate how physiological, pharmacological, and pathological conditions that alter sodium reabsorption (TNa) in the proximal tubule affect oxygen consumption (QO2 ) and Na(+) transport efficiency (TNa/QO2 ). 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 TNa/QO2 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 TNa and QO2 , as well as Na(+) transport efficiency. SGLT2 inhibition also reduced proximal tubular TNa but increased QO2 ; these effects were relatively more pronounced in the S3 vs. the S1-S2 segments. Diabetes increased TNa and QO2 and reduced TNa/QO2 , owing mostly to hyperfiltration. Since SGLT2 inhibition lowers diabetic hyperfiltration, the net effect on TNa, QO2 , and Na(+) transport efficiency in the proximal tubule will largely depend on the individual extent to which glomerular filtration rate is lowered.
authors: Department of Mathematics, Duke University, Durham, North Carolina; alayton@math.duke.edu.
authors: Anita T
authors: AT
authors: Layton
authors: Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, California, and San Diego Veterans Affairs Healthcare System, San Diego, California; and.
authors: Volker
authors: V
authors: Vallon
authors: Sorbonne Universités, Université Pierre et Marie Curie (UMPC) 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France.
authors: Aurélie
authors: A
authors: Edwards
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D003920:Diabetes Mellitus / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium
keywords: diabetes; glucose; metabolism; sodium transport