A mathematical model of rat ascending Henle limb. III. Tubular function.
K+ plays a catalytic role in AHL Na+ reabsorption via Na+-K+-2Cl- cotransporter (NKCC2), recycling across luminal K+ channels, so that luminal K+ is not depleted. Based on models of the ascending Henle limb (AHL) epithelium, it has been hypothesized that NH4+ may also catalyze luminal Na+ uptake. This hypothesis requires that luminal NH4+ not be depleted, implying replenishment via either direct secretion of NH4+, or NH3 in parallel with a proton. In the present work, epithelial models of rat medullary and cortical AHL (Weinstein AM, Krahn TA. Am J Physiol Renal Physiol 298: F000-F000, 2009) are configured as tubules and examined in simulations of function in vitro and in vivo to assess the feasibility of a catalytic role for NH4+ in Na+ reabsorption. Modulation of Na+ transport is also examined by peritubular K+ concentration and by Bartter-type transport defects in NKCC2 (type 1), in luminal membrane K+ channels (type 2), and in peritubular Cl- channels (type 3). It is found that a catalytic role for NH4+, which is significant in magnitude (relative to K+), is quantitatively realistic, in terms of uptake via NKCC2, and in terms of luminal membrane ammonia backflux. Simulation of a 90% NKCC2 defect is predicted to double distal Na+ delivery; it is also predicted to increase distal acid delivery (principally as NH4+). With doubling of medullary K+, the model predicts a 30% increase in distal Na+ delivery, but in this case there is a decrease in AHL acidification. This effect of peritubular K+ on proton secretion appears to be akin to type 3 Bartter's pathophysiology, in which there is decreased peritubular HCO3- exit, cytosolic alkalinization, and a consequent decrease in luminal proton secretion by NHE3. One consequence of overlapping and redundant roles for K+ and NH4+, is a blunted impact of luminal membrane K+ permeability on overall Na+ reabsorption, so that type 2 Bartter pathophysiology is not well captured by the model.
Weinstein
Alan M
AM
D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism; D002384:Catalysis; D002712:Chlorides / Q000378:metabolism; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008138:Loop of Henle / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010539:Permeability; D011188:Potassium / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1
D001639:Bicarbonates; D002712:Chlorides; D000644:Quaternary Ammonium Compounds; C578716:Slc12a1 protein, rat; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D012964:Sodium; D011188:Potassium