AI Article Synopsis
- Cyclosporin A (CSA) inhibits P-glycoprotein (ABCB1), but its link to CSA-induced kidney toxicity is not well understood.
- Three renal cell lines (LLC-PK1, MDCK, and Ma104) showed reduced viability with CSA treatment, with varying levels of resistance based on ABCB1 expression.
- CSA led to increased accumulation of the compound rhodamine 123 in all cell lines, suggesting that the nephrotoxicity of CSA may arise from both direct cellular injury and modulation of ABCB1 activity, resulting in toxic buildup of substrates.
Article Abstract
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.
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| http://dx.doi.org/10.1159/000083415 | DOI Listing |
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