Theory of Solute and Water Transport Across Epithelia

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PROJECT SUMMARY The overall project objective has been mathematical modeling of renal fluid and electrolyte transport in health and disease. Prior to the last period, this project had produced a model library of all kidney tubule segments, and the first task of the last period was to concatenate these segmental models into a nephron. The major effort of the last period was adding the medullary microcirculation, to advance the nephron to a kidney model, in which medullary composition was calculated, rather than specified. Simulation of major metabolic derangements (e.g. hyperglycemia, hyperkalemia, alkalosis), diuretic use, and genetic transport defects require a model of this scope. While, the kidney model captured overall solute excretion, interstitial concentration profiles and intratubular hydrostatic pressures need additional work. Specifically, medullary Na+ and urea and NH4+ concentrations were lower than expected; and changes in distal flow distorted pressures along the entire nephron. In the next period, Aim 1 preserves current model structure, and addresses Na+ and urea and pressure. It is expected that adjusting juxtamedullary nephron transport parameters will improve interstitial composition, and that revising tubular compliance will mitigate pressure effects. Aim 2 addresses renal NH4+ concentrations and partitioning of NH4+ flow between renal vein and urine. This cannot be done with parameter adjustments, but requires cortical microvasculature. It is expected that countercurrent exchange within cortical blood vessels can enhance ammonia excretion, while limiting renal venous ammonia (as seen in acidosis and liver disease). Aim 3 will be introduce calcium as a new model solute. Renal calcium concentration is a regulator of sodium transport, and of translational importance (e.g. hypercalciuric disorders, stone formation). Aim 4 comprises model application in experimental collaborations. Work continues with Dr. Tong Wang, examining the role of flow-dependent sodium reabsorption in renal cystic disease. A polycystic kidney disease gene may mediate this flow-response, and we suspect that failure to match fluxes to flows elevates tubule pressures, exacerbating cyst formation. In this regard, attention in Aim 1 to tubule pressures and compliance will be foundational for this aim. Collaboration is continuing with Dr. Larry Palmer to apply segmental and nephron models to K+ excretion in Na+-avid states. These experiments typically document changes in specific transporter densities, and the models provide a means of capturing these defects and estimating impact on other segments.