PPAR alpha-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Molecules; v. 25, n. 2 JAN 2 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 15/20082-7 - Sistema calicreína cininas no exercício físico e metabolismo
• Beneficiário: Ronaldo de Carvalho Araújo
• Modalidade de apoio: Auxílio à Pesquisa - Temático