PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2
Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/19/7416 |
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| author | Leandro Ceotto Freitas-Lima Alexandre Budu Adriano Cleis Arruda Mauro Sérgio Perilhão Jonatan Barrera-Chimal Ronaldo Carvalho Araujo Gabriel Rufino Estrela |
| author_facet | Leandro Ceotto Freitas-Lima Alexandre Budu Adriano Cleis Arruda Mauro Sérgio Perilhão Jonatan Barrera-Chimal Ronaldo Carvalho Araujo Gabriel Rufino Estrela |
| author_sort | Leandro Ceotto Freitas-Lima |
| collection | DOAJ |
| description | Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2. |
| first_indexed | 2024-03-10T15:47:01Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:47:01Z |
| publishDate | 2020-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bdc018d8796b42278a2aae4172714f5d2023-11-20T16:21:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012119741610.3390/ijms21197416PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2Leandro Ceotto Freitas-Lima0Alexandre Budu1Adriano Cleis Arruda2Mauro Sérgio Perilhão3Jonatan Barrera-Chimal4Ronaldo Carvalho Araujo5Gabriel Rufino Estrela6Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo 04039032, BrazilDepartamento de Biofísica, Universidade Federal de São Paulo, São Paulo 04039032, BrazilDepartamento de Biofísica, Universidade Federal de São Paulo, São Paulo 04039032, BrazilDepartamento de Biofísica, Universidade Federal de São Paulo, São Paulo 04039032, BrazilInstituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoDepartamento de Biofísica, Universidade Federal de São Paulo, São Paulo 04039032, BrazilDepartamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo, São Paulo 04039032, BrazilCisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.https://www.mdpi.com/1422-0067/21/19/7416cisplatin nephrotoxicityPPAR-alphaorganic transporters |
| spellingShingle | Leandro Ceotto Freitas-Lima Alexandre Budu Adriano Cleis Arruda Mauro Sérgio Perilhão Jonatan Barrera-Chimal Ronaldo Carvalho Araujo Gabriel Rufino Estrela PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2 International Journal of Molecular Sciences cisplatin nephrotoxicity PPAR-alpha organic transporters |
| title | PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2 |
| title_full | PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2 |
| title_fullStr | PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2 |
| title_full_unstemmed | PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2 |
| title_short | PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2 |
| title_sort | ppar α deletion attenuates cisplatin nephrotoxicity by modulating renal organic transporters mate 1 and oct 2 |
| topic | cisplatin nephrotoxicity PPAR-alpha organic transporters |
| url | https://www.mdpi.com/1422-0067/21/19/7416 |
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