Altered expression of tight junction proteins in cyclosporine nephrotoxicity.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Internal Medicine, Hanyang University College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Chang Hwa
CH
Lee
Sua
S
Kim
Chong Myung
CM
Kang
Wan Young
WY
Kim
Jin
J
Kim
Gheun-Ho
GH
Kim
D000818:Animals; D062445:Claudin-1; D062506:Claudin-4; D016572:Cyclosporine / Q000009:adverse effects*; D004285:Dogs; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D009399:Nephrons / Q000378:metabolism*; D062793:Occludin; D010750:Phosphoproteins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
D062445:Claudin-1; D062506:Claudin-4; C568114:Cldn1 protein, rat; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D016572:Cyclosporine