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Altered Expression of Tight Junction Proteins in Cyclosporine Nephrotoxicity

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Background/Aims: The increased permeability of chloride in the distal cortical nephron in cyclosporine nephrotoxicity may involve the transcellular pathway mediated by the thiazide-sensitive Na+-Cl? cotransporter and/or the paracellular pathway mediated by the tight junctions (TJs). Methods: Cyclosporine was subcutaneously administered to Sprague-Dawley rats for 6 (7.5 mg/kg body weight) and 2 (25 mg/kg body weight) weeks, and immunoblot analysis and immunohistochemistry were carried out from the kidneys. Electrically tight epithelial Madin-Darby canine kidney (MDCK) I cells were exposed to cyclosporine for 72 h to measure changes in transepithelial electrical resistance (ΔTER). Results: Cyclosporine treatment induced a decrease in Na+-Cl? cotransporter in rat renal cortex. WNK4 protein was increased in both rat kidneys and MDCK I cells. Occludin was also increased in rat kidneys and MDCK I cells exposed to 100 ng/ml cyclosporine. In contrast, cyclosporine treatment induced a decrease in zonula occludens 1 protein abundance and no changes in claudin-1 and claudin-4 in both rat kidneys and MDCK I cells. As a measure of the barrier to small ions, ΔTER of MDCK monolayers was decreased by 100 ng/ml cyclosporine. Conclusion: Renal TJ proteins are affected by cyclosporine treatment. Changes in TJ protein assembly induced by altered expression of WNK4, occludin, and zonula occludens 1 may affect paracellular permeability.This study was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund; KRF-2007-313-E00239)

Topics: Cyclosporine nephrotoxicity, Paracellular permeability, Sodium chloride symporter, Tight junction proteins, WNK4 protein
Publisher: KARGER
Year: 2011
DOI identifier: 10.1159/000322445
OAI identifier:
Provided by: HANYANG Repository
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