This project is designed to examine basic mechanisms by which important organic solutes, salt and water are reabsorbed by the mammalian proximal tubule, and how these processes are regulated under normal and pathologic conditions. Studies will employ the method of perfusing isolated rabbit and rat proximal convoluted and straight tubules. Some of the studies will incorporate the newly developed technique of perfusing these tubules under oil so that the primary absorbate may be sampled and analyzed. The following problems will be addressed: 1) The magnitude of the maximal transepithelial Na+ electrochemical potential gradient that can be developed in the presence of a poorly permeant luminal solute such as mannitol, and determination of the minimum work required to maintain this gradient. 2) The effect of different preferentially absorbed luminal solutes and transport inhibitors on the maximal Na+ gradient and work expenditure. 3) Measurements of transepithelial osmolality differences using a simple NaCl perfusate alone or in combination with preferentially absorbed solutes. 4) Measurements of reflection coefficients for NaCl, NaHCO3, glucose and amino acids. 5) The mechanism by which decreased luminal osmolality augments volume absorption. 6) The mechanisms by which adrenergic agents, PTH and angiotensin alter rates of salt and water absorption in various regions of the proximal nephron. 7) A study of the Na+ dependency and kinetics of basolateral amino acid active transport in the proximal straight tubule. Determination of whether this site may also serve for passive absorptive efflux. 8) Determination of the conditions under which luminal membrane sugar and amino acid carrier mechanisms may allow cell-to-lumen movement. 9) Effects of a chronic increase in filtered sugar and amino acid loads on the distribution of kinetically different transport sites along with the proximal nephron. 10) Development of mathematical models in connection with the above studies.
