THEORY OF SOLUTE AND WATER TRANSPORT ACROSS EPITHELIA

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A mathematical model of the mammalian collecting duct will be developed, comprised of cellular models of cortical, outer medullary and inner medullary segments. The model will represent Na+, K+, and acid/base transport under normal and pathological conditions, and will predict their renal excretion, given distal delivery. The initial focus will be parameter assignment for normal collecting duct function and during hormonal stimulation. Important redundancies have been identified in electrolyte transport pathways: luminal membrane Na+ flux via NaCl cotransport or Na+ -channel; H+ secretion via H+-ATPase or H+, K+-ATPase; peritubular base exit via c;-/HCO3- exchange or by means of NH4+ - NH3 recycling. This investigation will estimate these flux components, and identify experimental maneuvers which may be used to unambiguously conform these estimates. Particular attention will be paid to cell volume regulation, especially in inner medullary collecting duct, which can vary its Na+ transport rat from brisk reabsorption to secretion, and which faces a wide range in luminal fluid tonicity. Homeostatic control mechanisms have emphasized modulation of ion channel activity: luminal membrane Na+-channel and peritubular membrane K+ and C1- channels. Model simulations will examine feasibility of these proposed mechanisms, under both transient and steady state environmental perturbations., The second focus will be simulation of collecting duct dysfunction. In experimental models (ureteral obstruction, amiloride or lithium administration), specific segmental transport defects have been identified. The model will assess the adequacy of known defects to rationalize observed solute excretion patterns. Finally, the model will simulate clinical tests of distal nephron function (e.g. transtubular K+ gradient, impact of diuretics and impermeant anions on urinary pH). Such tests have traditionally been used to infer specific transport defects in patients with disorders of K+ metabolism or urinary acidification. This approach will be scrutinized by programming specific transport defects, subjecting the model to simulated testing, and assessing the ability to infer the defect.