Ammonia transport in a mathematical model of rat proximal tubule

Abstract

Pathways for ammonia transport have been incorporated within a model of rat proximal tubule [A. M. Weinstein. Am. J. Physiol. 263 (Renal Fluid Electrolyte Physiol. 32): F784-F798, 1992]. The luminal membrane includes a Na+/NH4+ exchanger, while at the peritubular membrane there is uptake of NH4+ on the Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase); both luminal and peritubular cell membranes contain conductive pathways for NH4+. The model equations have been expanded to include cellular ammoniagenesis. The principal focus of this study is the interplay of forces that can raise proximal tubule fluid total ammonia concentration 10-fold higher than in arterial plasma. Analysis of a cellular model reveals that luminal membrane Na+/NH4+ exchange, cellular production of ammonia, and peritubular membrane NH4+ uptake (via Na(+)-K(+)-ATPase or via K+ channel) all act in parallel to drive ammonia secretion. This derives from the cellular interconversion of NH4+ and NH3 and the free permeation of NH3 across cell membranes. It implies that inhibition of the luminal membrane transporter does not block the contribution of peritubular uptake to the overall active transport of ammonia. Conversely, when inhibition of the luminal membrane Na+/NH4+ entry (i.e., Na+/H+ inhibition) depresses transcellular Na+ flux, then the decrease of NH4+ flux through the peritubular Na+ pump enhances the apparent importance of the luminal membrane pathway. This analysis is confirmed in the numerical calculations and is a departure from the Ussing paradigm of series membrane Na+ transport. Although active secretion of ammonia by this tubule is substantial, the relative contribution of luminal Na+/NH4+ exchange and of peritubular uptake via the Na+ pump remains uncertain. The determination of peritubular capillary NH4+ concentration will be crucial to resolving this uncertainty, with lower concentration (i.e., closer to systemic arterial ammonia) obligating greater luminal membrane Na+/NH4+ exchange.