Effects of NKCC2 isoform regulation on NaCl transport in thick ascending limb and macula densa: a modeling study.
This study aims to understand the extent to which modulation of the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 differential splicing affects NaCl delivery to the macula densa. NaCl absorption by the thick ascending limb and macula densa cells is mediated by apical NKCC2. A recent study has indicated that differential splicing of NKCC2 is modulated by dietary salt (Schieβl IM, Rosenauer A, Kattler V, Minuth WW, Oppermann M, Castrop H. Am J Physiol Renal Physiol 305: F1139-F1148, 2013). Given the markedly different ion affinities of its splice variants, modulation of NKCC2 differential splicing is believed to impact NaCl reabsorption. To assess the validity of that hypothesis, we have developed a mathematical model of macula densa cell transport and incorporated that cell model into a previously applied model of the thick ascending limb (Weinstein AM, Krahn TA. Am J Physiol Renal Physiol 298: F525-F542, 2010). The macula densa model predicts a 27.4- and 13.1-mV depolarization of the basolateral membrane [as a surrogate for activation of tubuloglomerular feedback (TGF)] when luminal NaCl concentration is increased from 25 to 145 mM or luminal K(+) concentration is increased from 1.5 to 3.5 mM, respectively, consistent with experimental measurements. Simulations indicate that with luminal solute concentrations consistent with in vivo conditions near the macula densa, NKCC2 operates near its equilibrium state. Results also suggest that modulation of NKCC2 differential splicing by low salt, which induces a shift from NKCC2-A to NKCC2-B primarily in the cortical thick ascending limb and macula densa cells, significantly enhances salt reabsorption in the thick limb and reduces Na(+) and Cl(-) delivery to the macula densa by 3.7 and 12.5%, respectively. Simulation results also predict that the NKCC2 isoform shift hyperpolarizes the macula densa basolateral cell membrane, which, taken in isolation, may inhibit the release of the TGF signal. However, excessive early distal salt delivery and renal salt loss during a low-salt diet may be prevented by an asymmetric TGF response, which may be more sensitive to flow increases.
University of Paris 6, University of Paris 5, Institut National de la Santé et de la Recherche Médicale UMRS 1138, Centre National de la Recherche Scientifique ERL 8228, Centre de Recherche des Cordeliers, Paris, France;
Aurélie
A
Edwards
Institute of Physiology University of Regensburg, Regensburg, Germany;
Hayo
H
Castrop
University of Paris 6, University of Paris 5, Institut National de la Santé et de la Recherche Médicale UMRS 1138, Centre National de la Recherche Scientifique ERL 8228, Centre de Recherche des Cordeliers, Paris, France;
Kamel
K
Laghmani
Departments of Medicine and Pharmacology, University of California, San Diego, La Jolla, California, and San Diego Veterans Affairs Healthcare System, San Diego, California; and.
Volker
V
Vallon
Department of Mathematics, Duke University, Durham, North Carolina alayton@math.duke.edu.
Anita T
AT
Layton
D000042:Absorption; D000818:Animals; D001692:Biological Transport; D003198:Computer Simulation; D004039:Diet, Sodium-Restricted; D006706:Homeostasis; D008138:Loop of Henle / Q000378:metabolism*; D008564:Membrane Potentials; D008954:Models, Biological; D020033:Protein Isoforms; D051381:Rats; D012965:Sodium Chloride / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism*
D020033:Protein Isoforms; C578716:Slc12a1 protein, rat; D064466:Solute Carrier Family 12, Member 1; D012965:Sodium Chloride
blood pressure; differential splicing; epithelial transport; low-salt diet; mathematical modeling; salt homeostasis; tubuloglomerular feedback