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. the focus is on the handling of Na, K, urea, and water and their control by various cellular mechanisms.
Specific aims are: 1. To model those segments not yet modeled: proximal straight tubule (PST), descending thin limb (DTL), ascending thin limb (ATL), distal convoluted tubule (DCT), connecting tubule (CNT), and outer and inner medullary collecting duct (OMCD & IMCD). the models will be based on existing models of proximal convoluted tubule (PCT), thick ascending limb of Henle's loop (TAL), and cortical collecting tubule (CCT) and will include both cellular and paracellular pathways and the following variables: Na+, K+, Cl-, urea, hydrostatic pressure, and electric potential. For some segments the models will include the additional variables H+, HCO3-, HPO4--, H2P04-, NH4+, NH3, Ca++, Mg++, glucose, and possibly organic osmolytes. 2. To synthesize the segmental models first into a model of the loop of Henle, which will be used to interpret in vivo perfusion data, and then together with a model of PT and post-glomerular capillary into a model of a cortical nephron, which will be used to interpret free flow cortical micropuncture data. 3. To use the models of DTL, ATL, and IMCD to explore possible new mechanisms of concentration for the renal inner medulla: in particular the thermodynamic feasibility and possible role of urea-electrolyte cotransport systems driving electrolyte cycling from ATL to DTL. 4. To model the cable properties of the various nephron segments in terms of cellular and paracellular transport processes. 5. To extend the segmental models to include Ca++ and Mg++. Here we will focus primarily on developing a model of calcium handling by the principal cell of CCT and the role of cytosolic Ca++ in modulating its apical Na+ permeability. If a sufficient data base emerges we will also develop possible models for Mg++ handling by TAL. Here a hypothesis to be tested is that cytosolic Mg regulates activity of the K:Na:2Cl cotransporter.
