After a detailed description of early cellular, membrane and intracellular events in rat renal medullary collecting duct cells when exposed to hypotonicity, a synopsis on organic osmolyte transport properties, possible trigger mechanisms, and the cellular location of transport pathways is given. From the data currently available on renal and nonrenal cells, it is concluded that hypotonicity-evoked efflux of all organic osmolytes appears to be mediated by transport proteins which share a variety of properties more typical for channels than for carriers. A large diversity seems to exist, however, for the signalling mechanisms. Such diversity allows the cells to regulate the intracellular concentration of different organic osmolytes independently of each other, giving flexibility to the spectrum of osmotic responses. The site of release also varies from cell to cell; here conservation of organic osmolytes for future reuptake or further metabolism appears to be the major determinant.

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Effect of cyclosporine A on Na+/K(+)-ATPase, Na+/K+/2Cl- cotransporter, and H+/K(+)-ATPase in MDCK cells and two subtypes, C7 and C11.

We investigated the influence of cyclosporine A (CsA) on key plasma membrane ion transport systems Na+/K(+)-ATPase, Na+/K+/2Cl- cotransporter, and H+/K(+)-ATPase in MDCK cells and two subtypes, C7 and C11, serving as a model system to study principal (C7) and intercalated (C11) cell properties of the distal nephron. The transport activity of Na+/K(+)-ATPase was significantly decreased in all cell types on CsA administration (8 x 10(-6) M) for 2 days, whereas the protein levels of Na+/K(+)-ATPase alpha-subunit in plasma membranes isolated from MDCK, C7, and C11 cells remained unchanged. The transport activity of Na+/K+/2Cl- cotransporter was significantly inhibited by CsA only in MDCK and C11 cells, but again plasma membrane protein levels were not altered. In contrast, C7 cell plasma membranes showed an increase of transport protein content, although the Na+/K+/2Cl- cotransporter activity was not affected by CsA. The H+/K(+)-ATPase transport activity remained unchanged in all three cell types. These data indicate that in C7 cells CsA might induce insertion of transporters into the plasma membrane, thus compensating the decrease of transport activity observed in MDCK and C11 cells. Furthermore, CsA significantly inhibited cell proliferation at 4 x 10(-6) M for C7 and C11 cells and at 8 x 10(-6) M for MDCK cells. Proliferation was completely abolished at 1.6 x 10(-5) M CsA. After 48 h of CsA incubation, the intracellular sodium concentration increased in all three different cell types; however, it stayed within the physiological range of mammalian cells. We, therefore, suggest that CsA is capable of reducing Na+/K(+)-ATPase and Na+/K+/2Cl- cotransporter activities in cells of the distal nephron, thereby contributing to the hyperkalemia observed in patients treated with CsA.

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