The primary goal is to advance understanding of the functional and structural relationships in the mammalian renal inner medulla by determining: 1) the process and regulation of amino acid and osmolyte transport and recycling among papillary thin limbs of Henle's loops and vasa recta, including regulation by vasa recta; 2) the relationship of structure and structural organization of papillary thin limbs to function, including development of the inner medullary osmotic gradient; and 3) the relationship of extracellular environment to function, including regulation of intracellular pH, in the papillary thin limbs. Regulated inner medullary recycling of taurine and other osmolytes may be important for maintaining appropriate extracellular concentrations for cellular accumulation. Observations suggesting regulation of recycling by the vasa recta suggest a significant new role for these vessels in the inner medulla. Observations demonstrating that segments of inner medullary descending thin limbs have cells with the appearance and function of cells in ascending thin limbs and vice versa suggest that the architectural arrangement of such segments may be critical for determining inner medullary osmotic and ionic gradients. Observations that intracellular pH of papillary thin limbs is related to pH and composition of extracellular environment indicate the significance of the extracellular composition for cellular regulatory processes. The planned studies will take advantage of techniques for studying both in vivo and in vitro equivalent segments of thin limbs of Henle's loops and vasa recta from Munich-Wistar rats. They will involve: 1) flux measurements during in vivo continuous microinfusions of papillary loops of Henle and vasa recta and microperfusions of papillary vasa recta; 2) flux measurements during in vitro microperfusions of papillary descending and ascending thin limbs and ascending vasa recta; 3) determination of the architectural arrangement (via systematic teasing, confocal microscopic analysis, and scanning electron microscopic analysis), and integrative function (via RT-PCR, immunocytochemistry, perfusion flux measurements, and mathematical modeling) of ascending-type segments in descending thin limbs and descending-type segments in ascending thin limbs; and 4) determination of regulation of intracellular pH in papillary thin limbs and its relationship to extracellular environment and to thin limb function.
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