| Full text | |
| Author(s): |
Arruda, Adriano Cleis
[1]
;
Perilhao, Mauro Sergio
[1]
;
Santos, Warley Almeida
[1]
;
Gregnani, Marcos Fernandes
[1]
;
Budu, Alexandre
[1]
;
Rosa Neto, Jose Cesar
[2]
;
Estrela, Gabriel Rufino
[3]
;
Araujo, Ronaldo Carvalho
[1]
Total Authors: 8
|
| Affiliation: | [1] Univ Fed Sao Paulo, Dept Biophys, BR-04039032 Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Cell Biol & Dev, BR-05508000 Sao Paulo - Brazil
[3] Univ Fed Sao Paulo, Discipline Hematol & Haematotherapy, Dept Clin & Expt Oncol, BR-04037002 Sao Paulo - Brazil
Total Affiliations: 3
|
| Document type: | Journal article |
| Source: | Molecules; v. 25, n. 2 JAN 2 2020. |
| Web of Science Citations: | 0 |
| Abstract | |
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 (PPAR alpha). 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 PPAR alpha and OCT-2 expression by 37% and 299% respectively. MK-886, a PPAR alpha antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPAR alpha, elicited the increase of PPAR alpha, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPAR alpha knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPAR alpha-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 PPAR alpha, and this effect may have implications for drug safety and efficacy. (AU) | |
| FAPESP's process: | 15/20082-7 - Kallikrein kinin system in physical exercise and metabolism |
| Grantee: | Ronaldo de Carvalho Araújo |
| Support Opportunities: | Research Projects - Thematic Grants |