Comparative study on the effects of cyclosporin a in renal cells in culture.
BACKGROUND
Although cyclosporin A (CSA) inhibits P-glycoprotein (ABCB1), the relationship between this inhibition and CSA-induced nephrotoxicity is not established.


METHODS
Three renal cell lines were used to investigate the effects of CSA in cellular viability and accumulation of rhodamine 123 (Rho123): LLC-PK1, which does not express ABCB1 substantially; MDCK, expressing moderate amounts of this protein, and Ma104 cells, which express high amounts of ABCB1.


RESULTS
The viability was significantly reduced in the three cell lines after treatment with CSA concentrations >10 microM. Ma104 was the more resistant and LLC-PK1 the more sensitive. CSA increased Rho123 accumulation in the three cell lines when incubated simultaneously, MDCK presenting the higher increase. However, different results were achieved when the periods of incubation with Rho123 and CSA were disconnected: a post-incubation with CSA was more effective in Ma104 cells, while MDCK and LLC-PK1 showed no difference between pre-, co- and post-incubation with CSA.


CONCLUSIONS
Our results suggest that the effects of CSA may be divided into two groups: ABCB1-independent (direct injury), and ABCB1-dependent toxicity, due to modulation of its activity. This could result in increased accumulation of noxious ABCB1 substrates, contributing to CSA-induced nephrotoxicity. Furthermore, the mechanisms of ABCB1 modulation by CSA may be different for different cell lines.
Nascimento
Clarissa R
CR
Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil.
Braga
Filipe
F
Capella
Luiz S
LS
Santos
Omar R
OR
Lopes
Aníbal G
AG
Capella
Marcia A M
MA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004285:Dogs; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D018374:LLC-PK1 Cells; D008253:Macaca mulatta; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000447:Aldehydes; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; C111472:mitotracker green FM; D020112:Rhodamine 123; D016572:Cyclosporine