PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice
Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent u...
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MDPI AG
2020-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/2/392 |
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| author | Adriano Cleis Arruda Mauro Sérgio Perilhão Warley Almeida Santos Marcos Fernandes Gregnani Alexandre Budu José Cesar Rosa Neto Gabriel Rufino Estrela Ronaldo Carvalho Araujo |
| author_facet | Adriano Cleis Arruda Mauro Sérgio Perilhão Warley Almeida Santos Marcos Fernandes Gregnani Alexandre Budu José Cesar Rosa Neto Gabriel Rufino Estrela Ronaldo Carvalho Araujo |
| author_sort | Adriano Cleis Arruda |
| collection | DOAJ |
| description | Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy. |
| first_indexed | 2024-12-20T03:00:24Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T03:00:24Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-26acfe0eb242492ea9d17ba97418b7572022-12-21T19:55:46ZengMDPI AGMolecules1420-30492020-01-0125239210.3390/molecules25020392molecules25020392PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of MiceAdriano Cleis Arruda0Mauro Sérgio Perilhão1Warley Almeida Santos2Marcos Fernandes Gregnani3Alexandre Budu4José Cesar Rosa Neto5Gabriel Rufino Estrela6Ronaldo Carvalho Araujo7Department of Biophysics, Federal University of São Paulo, 04039032 São Paulo, BrazilDepartment of Biophysics, Federal University of São Paulo, 04039032 São Paulo, BrazilDepartment of Biophysics, Federal University of São Paulo, 04039032 São Paulo, BrazilDepartment of Biophysics, Federal University of São Paulo, 04039032 São Paulo, BrazilDepartment of Biophysics, Federal University of São Paulo, 04039032 São Paulo, BrazilDepartment Cell Biology and Development, Institute of Biomedical Sciences, University of São Paulo, 05508000 São Paulo, BrazilDepartment of Clinical and Experimental Oncology, Discipline of Hematology and Haematotherapy, Federal University of São Paulo, 04037002 São Paulo, BrazilDepartment of Biophysics, Federal University of São Paulo, 04039032 São Paulo, BrazilMetformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.https://www.mdpi.com/1420-3049/25/2/392metforminpparαmate-1oct-2transcriptionkidney |
| spellingShingle | Adriano Cleis Arruda Mauro Sérgio Perilhão Warley Almeida Santos Marcos Fernandes Gregnani Alexandre Budu José Cesar Rosa Neto Gabriel Rufino Estrela Ronaldo Carvalho Araujo PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice Molecules metformin pparα mate-1 oct-2 transcription kidney |
| title | PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice |
| title_full | PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice |
| title_fullStr | PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice |
| title_full_unstemmed | PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice |
| title_short | PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice |
| title_sort | pparα dependent modulation by metformin of the expression of oct 2 and mate 1 in the kidney of mice |
| topic | metformin pparα mate-1 oct-2 transcription kidney |
| url | https://www.mdpi.com/1420-3049/25/2/392 |
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