Therapeutic concentrations of calcineurin inhibitors do not deregulate glutathione redox balance in human renal proximal tubule cells

被引:7
作者
Ramazani, Yasaman [1 ]
Knops, Noel [1 ,2 ]
Berlingerio, Sante Princiero [1 ]
Adebayo, Oyindamola Christiana [1 ]
Lismont, Celien [3 ]
Kuypers, Dirk J. [4 ,5 ]
Levtchenko, Elena [1 ,2 ]
van den Heuvel, Lambert P. [1 ,6 ,7 ]
Fransen, Marc [3 ]
机构
[1] Univ Leuven, Dept Growth & Regenerat, Lab Pediat Nephrol, Leuven, Belgium
[2] Univ Hosp Leuven, Dept Pediat Nephrol & Solid Organ Transplantat, Leuven, Belgium
[3] Univ Leuven, Dept Cellular & Mol Med, Lab Peroxisome Biol & Intracellular Commun, Leuven, Belgium
[4] Univ Leuven, Dept Nephrol & Renal Transplantat, Leuven, Belgium
[5] Univ Leuven, Dept Microbiol Immunol & Transplantat, Leuven, Belgium
[6] Radboud Univ Nijmegen, Med Ctr, Translat Metab Lab, Nijmegen, Netherlands
[7] Radboud Univ Nijmegen, Med Ctr, Dept Pediat Nephrol, Nijmegen, Netherlands
来源
PLOS ONE | 2021年 / 16卷 / 04期
关键词
TACROLIMUS-INDUCED NEPHROTOXICITY; OXIDATIVE STRESS; CYCLOSPORINE-A; MAMMALIAN-CELLS; TRANSPLANTATION; MITOCHONDRIAL; KIDNEY; DYSFUNCTION; VALIDATION; EXPRESSION;
D O I
10.1371/journal.pone.0250996
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The calcineurin inhibitors (CNI) cyclosporine A and tacrolimus comprise the basis of immunosuppressive regimes in all solid organ transplantation. However, long-term or high exposure to CNI leads to histological and functional renal damage (CNI-associated nephrotoxicity). In the kidney, proximal tubule cells are the only cells that metabolize CNI and these cells are believed to play a central role in the origin of the toxicity for this class of drugs, although the underlying mechanisms are not clear. Several studies have reported oxidative stress as an important mediator of CNI-associated nephrotoxicity in response to CNI exposure in different available proximal tubule cell models. However, former models often made use of supra-therapeutic levels of tissue drug exposure. In addition, they were not shown to express the relevant enzymes (e.g., CYP3A5) and transporters (e.g., P-glycoprotein) for the metabolism of CNI in human proximal tubule cells. Moreover, the used methods for detecting ROS were potentially prone to false positive results. In this study, we used a novel proximal tubule cell model established from human allograft biopsies that demonstrated functional expression of relevant enzymes and transporters for the disposition of CNI. We exposed these cells to CNI concentrations as found in tissue of stable solid organ transplant recipients with therapeutic blood concentrations. We measured the glutathione redox balance in this cell model by using organelle-targeted variants of roGFP2, a highly sensitive green fluorescent reporter protein that dynamically equilibrates with the glutathione redox couple through the action of endogenous glutaredoxins. Our findings provide evidence that CNI, at concentrations commonly found in allograft biopsies, do not alter the glutathione redox balance in mitochondria, peroxisomes, and the cytosol. However, at supra-therapeutic concentrations, cyclosporine A but not tacrolimus increases the ratio of oxidized/reduced glutathione in the mitochondria, suggestive of imbalances in the redox environment.
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页数:17
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