Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling
Abstract Calcineurin inhibitors (CNI) are the pillars of immunosuppression in transplantation. However, they display a potent nephrotoxicity whose mechanisms remained widely unsolved. We used an untargeted quantitative proteomic approach (iTRAQ technology) to highlight new targets of CNI in renal pr...
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doaj-5e8946918e97447cbb33ca516da592002020-11-24T22:01:02ZengWileyFASEB BioAdvances2573-98322019-09-011956157810.1096/fba.2019-00027Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodelingBastien Burat0Quentin Faucher1Petra Čechová2Hélène Arnion3Florent Di Meo4François‐Ludovic Sauvage5Pierre Marquet6Marie Essig7Centre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceCentre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceDepartment of Biophysics, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science Palacký University Olomouc Olomouc Czech RepublicCentre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceCentre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceCentre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceCentre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceCentre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges FranceAbstract Calcineurin inhibitors (CNI) are the pillars of immunosuppression in transplantation. However, they display a potent nephrotoxicity whose mechanisms remained widely unsolved. We used an untargeted quantitative proteomic approach (iTRAQ technology) to highlight new targets of CNI in renal proximal tubular cells (RPTCs). CNI‐treated RPTCs proteome displayed an over‐representation of actin‐binding proteins with a CNI‐specific expression profile. Cyclosporine A (CsA) induced F‐actin remodeling and depolymerization, decreased F‐actin‐stabilizing, polymerization‐promoting cofilin (CFL) oligomers, and inhibited the G‐actin‐regulated serum response factor (SRF) pathway. Inhibition of CFL canonical phosphorylation pathway reproduced CsA effects; however, S3‐R, an analogue of the phosphorylation site of CFL prevented the effects of CsA which suggests that CsA acted independently from the canonical CFL regulation. CFL is known to be regulated by the Na+/K+‐ATPase. Molecular docking calculations identified two inhibiting sites of CsA on Na+/K+‐ATPase and a 23% decrease in Na+/K+‐ATPase activity of RPTCs was observed with CsA. Ouabain, a specific inhibitor of Na+/K+‐ATPase also reproduced CsA effects on actin organization and SRF activity. Altogether, these results described a new original pathway explaining CsA nephrotoxicity.https://doi.org/10.1096/fba.2019-00027actin cytoskeletoncofilincyclosporine AMRTF‐SRFNa+/K+‐ATPase |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bastien Burat Quentin Faucher Petra Čechová Hélène Arnion Florent Di Meo François‐Ludovic Sauvage Pierre Marquet Marie Essig |
spellingShingle |
Bastien Burat Quentin Faucher Petra Čechová Hélène Arnion Florent Di Meo François‐Ludovic Sauvage Pierre Marquet Marie Essig Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling FASEB BioAdvances actin cytoskeleton cofilin cyclosporine A MRTF‐SRF Na+/K+‐ATPase |
author_facet |
Bastien Burat Quentin Faucher Petra Čechová Hélène Arnion Florent Di Meo François‐Ludovic Sauvage Pierre Marquet Marie Essig |
author_sort |
Bastien Burat |
title |
Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling |
title_short |
Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling |
title_full |
Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling |
title_fullStr |
Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling |
title_full_unstemmed |
Cyclosporine A inhibits MRTF‐SRF signaling through Na+/K+ ATPase inhibition and actin remodeling |
title_sort |
cyclosporine a inhibits mrtf‐srf signaling through na+/k+ atpase inhibition and actin remodeling |
publisher |
Wiley |
series |
FASEB BioAdvances |
issn |
2573-9832 |
publishDate |
2019-09-01 |
description |
Abstract Calcineurin inhibitors (CNI) are the pillars of immunosuppression in transplantation. However, they display a potent nephrotoxicity whose mechanisms remained widely unsolved. We used an untargeted quantitative proteomic approach (iTRAQ technology) to highlight new targets of CNI in renal proximal tubular cells (RPTCs). CNI‐treated RPTCs proteome displayed an over‐representation of actin‐binding proteins with a CNI‐specific expression profile. Cyclosporine A (CsA) induced F‐actin remodeling and depolymerization, decreased F‐actin‐stabilizing, polymerization‐promoting cofilin (CFL) oligomers, and inhibited the G‐actin‐regulated serum response factor (SRF) pathway. Inhibition of CFL canonical phosphorylation pathway reproduced CsA effects; however, S3‐R, an analogue of the phosphorylation site of CFL prevented the effects of CsA which suggests that CsA acted independently from the canonical CFL regulation. CFL is known to be regulated by the Na+/K+‐ATPase. Molecular docking calculations identified two inhibiting sites of CsA on Na+/K+‐ATPase and a 23% decrease in Na+/K+‐ATPase activity of RPTCs was observed with CsA. Ouabain, a specific inhibitor of Na+/K+‐ATPase also reproduced CsA effects on actin organization and SRF activity. Altogether, these results described a new original pathway explaining CsA nephrotoxicity. |
topic |
actin cytoskeleton cofilin cyclosporine A MRTF‐SRF Na+/K+‐ATPase |
url |
https://doi.org/10.1096/fba.2019-00027 |
work_keys_str_mv |
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