Paracellular permeability changes may be important in the pathophysiology of renal diseases such as salt-sensitive hypertension and ischemic acute renal failure. Our previous work and that of others suggest that the claudins, a family of tight junction proteins, may mediate paracellular permeability along the renal tubule. To further our studies of the biology of renal claudins, we have developed a renal cell line that overexpresses a distal tubule claudin, claudin-8, and incorporates it into tight junctions. Hypothesis: Claudin-8 functions as a high-resistance ion channel that presents a barrier to monovalent anions and cations, and to divalent cations.
Specific Aims to test this hypothesis are: Characterize the structural and functional effects of incorporation of claudin-8 into tight juctions in vitro. Methods to be used include Ussing chamber studies of diffusion potentials and ion fluxes, freeze fracture, and molecular chemistry and localization of junctional proteins. These data will be used to generate a model to explain the functional role of claudin-8 in mediating paracellular permeability.
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