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 N⁺ reabsorption. Modulation of N⁺ 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 N⁺ 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 N⁺ delivery, but in this case there is a decrease in AHL acidification. This effect of peritubular 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 N⁺ reabsorption, so that type 2 Bartter pathophysiology is not well captured by the model. [ABSTRACT FROM AUTHOR]