Interference of cyclosporine on glucose metabolism: potential role in chronic transplantation kidney fibrosis.
OBJECTIVE
To explore the fibrosis induction effects of cyclosporine (CsA) on renal tubular epithelial cells, as well as the potential mechanisms of CsA-mediated alterations of glucose metabolism in chronic allograft nephropathy (CAN).


METHODS
The rat renal tubular epithelial cell line NRK-52E cells were cultured in medium with 50 mmol/L of D-glucose for 7, 14, or 28 days. The expression of TGF-beta1, CTGF, Smad3, and Smad7, which are involved in the fibrosis signal pathway, was detected by immunofluorescence and reverse-transcriptase polymerase chain reaction. Meanwhile, cells were cultured in various concentration of CsA in glucose-free medium for 24 hours followed by the addition of D-[3-(3)H]-glucose for 30 minutes; glucose uptake was detected by examining the radiation intensity.


RESULTS
The expression of TGF-beta1, Smad3, Smad7, and CTGF of NRK-52E cells were up-regulated significantly (P < .05) after culture with 50 mmol/L glucose for 7 days compared with those in 25 mmol/L glucose. At 14 and 28 days, TGF-beta1 was slightly decreased compared with 7 days, but CTGF, Smad3, and Smad7 increased robustly (P < .05). CsA significantly stimulated glucose uptake at various concentrations, with an absorption peak at 60 minutes that decreased at 75 minutes. Furthermore, CsA may have dose-dependent effects on glucose uptake.


CONCLUSIONS
High glucose concentrations may play an important role in the NRK-52E cell fibrosis during the CAN process due to an interference of CsA on glucose metabolism.
Qiu
J
J
Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
Tu
Z
Z
Shi
Y
Y
Zhang
L
L
Li
Q
Q
Wang
W
W
Ye
F
F
Wang
J
J
Bu
H
H
D000818:Animals; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine / Q000494:pharmacology*; D005355:Fibrosis; D005643:Fucose / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D016030:Kidney Transplantation / Q000473:pathology*; D007684:Kidney Tubules; D011183:Postoperative Complications / Q000473:pathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics; D051906:Smad7 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism*
C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D005643:Fucose; D016572:Cyclosporine; D005947:Glucose