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Cadmium induced change in ion transport and cell signaling in cultured kidney distal epithelial cells (A6)
Henning F. Bjerregaard, University of Roskilde, Department of Science, Systems and Models, 4000 Roskilde, Denmark. HFB@ RUC.DK
Cadmium (Cd) is an important industrial and environmental pollutant. It have been estimated that 7% of the human population may develop renal dysfunction from Cd exposure. Chronic exposure to Cd results in dysfunction of the proximal tubule, however relatively little is known regarding the mechanisms by which Cd affect the epithelial cells of the distal tubule. To elucidate the effect of cadmium on ion transport and cell signaling inepithelial cells from the distal part of the kidney, A6 cells were used, since this cell model exhibits the morphological and functional properties of the mammalian distal epithelium.
Addition of Cd2+ to the basolateral (but not apical) solution of A6 epithelia resulted in a dose dependent increase in active ion transports, measured as short circuit current (SCC). The Cd2+ induced increase in SCC was not affected by the sodium channel inhibitor amiloride in the apical solution, indicating that increase in SCC was due to a stimulation of the chloride secretion. In order to investigate post-receptor signal transduction events, the effect of Cd2+ on (Ca2+)i homeostasis was examined in A6 cells loaded with fura-2. Cd2+ produced a large transient hormone-like spike in (Ca2+)i in a dose-dependent manner. The PLC-inhibitor U73122 and neomycin, both affected Cd2+-evoked increase in (Ca2+)i . These results indicate that A6 cells possess a divalent cation receptor in the basolateral membrane, which is able to stimulate phospholipase C, thereby increase the production of inositol triphosphate leading to increased (Ca2+)i, which activate specific chloride channels in the apical membrane
Since calcium signaling plays a crucial role in virtually all cellular processes including cell proliferation, progression through the cell cycle and cell death, these objectives have been studied during short time (acute) and long time cadmium exposure. Lately we have investigated the relation between cadmium induced increase in cell calcium and generation of reactive oxygen species from mitochondria.
3 feb. 2008
Regulation of Transcellular Transport: Nordforsk-network meeting in Membrane Transport Physiology.