The overall aim in this continuing project is to integrate experimental data on water and solute transport at the membrane level into a predictive model of whole kidney function that is useful in both experimental design and patient management. During this period the focus is on the handling of Na, K, urea, and water and their control by ADH and aldosterone.
The specific aims are: 1. To model thick ascending limb of Henle's loop (TAHL). This model, based on models to toad bladder and proximal tubule (PT), will include both cellular and paracellular pathways and the following variables: Na+, K+, Cl-, urea, hydrostatic pressure, electric potential, and volume flow; it may also include the additional variables H+, HCO3+, HPO42-, H2PO4-, NH4+, and glucose and will utilize a linear non-equilibrium thermodynamic (NET) formalism to describe fluxes. A primary objective will be to understand transmural fluxes of Na+, K+, Cl- and NH4+ in terms of apical and basolateral membrane transport systems. Another will be to model the target action of ADH and diuretics on the apical co-transport system. 2. To incorporate the TAHL model together with the PT model into a central core model of the cortex and outer medulla. The extended model will be used to interpret cortical micropuncture data and certain clearance data, particularly from the isolated perfused kidney. 3. To model the cortical collecting tubule (CCT). By including the carbonic anhydrase (CA)-rich intercalated cell, this will be the first model of a cellularly heterogeneous epithelium. The model will be used to explore K+ handling, H+ secretion, HCO3-secretion, water absorption and their control and interaction in the experimentally isolated and perfused tubule, and will also be incorporated into the central core model of a cortical nephron. 4. To develop models of descending (DHL) and ascending (AHL) thin limbs of the loop of Henle that include cellular and paracellular pathways. These models will be used to explore the hypothesis that cycling of potassium from AHL to DHL generates the inner medullary concentration gradient. 5. To extend a two nephron model of the medulla to a) include the extended segmental models and b) to incorporate additional details of the architectural organization of the medulla; and to develop and to utilize new methods of parameter estimation.
