title: Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors.
abstract: Sodium and its associated anions are the major determinant of extracellular fluid volume, and the reabsorption of Na+by the kidney plays a crucial role in long-term blood pressure control. The goal of this study was to investigate the extent to which inhibitors of transepithelial Na+transport (TNa) along the nephron alter urinary solute excretion and TNaefficiency and how those effects may vary along different nephron segments. To accomplish that goal, we used the multinephron model developed in the companion study (28). That model represents detailed transcellular and paracellular transport processes along the nephrons of a rat kidney. We simulated the inhibition of the Na+/H+exchanger (NHE3), the bumetanide-sensitive Na+-K+-2Cl-transporter (NKCC2), the Na+-Cl-cotransporter (NCC), and the amiloride-sensitive Na+channel (ENaC). Under baseline conditions, NHE3, NKCC2, NCC, and ENaC reabsorb 36, 22, 4, and 7%, respectively, of filtered Na+The model predicted that inhibition of NHE3 substantially reduced proximal tubule TNaand oxygen consumption (QO2). Whole-kidney TNaefficiency, as reflected by the number of moles of Na+reabsorbed per moles of O2consumed (denoted by the ratio TNa/QO2), decreased by ∼20% with 80% inhibition of NHE3. NKCC2 inhibition simulations predicted a substantial reduction in thick ascending limb TNaand QO2; however, the effect on whole-kidney TNa/QO2was minor. Tubular K+transport was also substantially impaired, resulting in elevated urinary K+excretion. The most notable effect of NCC inhibition was to increase the excretion of Na+, K+, and Cl-; its impact on whole-kidney TNaand its efficiency was minor. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+(increased) and K+(decreased) and to have only a minor impact on whole-kidney TNaand TNa/QO2Overall, model predictions agree well with measured changes in Na+and K+excretion in response to diuretics and Na+transporter mutations.
authors.affiliation: Department of Mathematics, Duke University, Durham, North Carolina; alayton@math.duke.edu.
authors.forename: Anita T
authors.initials: AT
authors.lastname: Layton
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France; and.
authors.forename: Kamel
authors.initials: K
authors.lastname: Laghmani
authors.affiliation: Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, California, and San Diego Veterans Affairs Healthcare System, San Diego, California.
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France; and.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Edwards
mesh_terms: D000818:Animals; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D008954:Models, Biological; D009399:Nephrons / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D064466:Solute Carrier Family 12, Member 1 / Q000037:antagonists & inhibitors*
chemical_list: D062686:Epithelial Sodium Channel Blockers; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D064466:Solute Carrier Family 12, Member 1
keywords: ENaC; NCC; NH3; NKCC2; oxygen consumption; sodium transport