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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Published in:Molecules (Basel, Switzerland) Switzerland), 2020-01, Vol.25 (2), p.392
Main Authors: Arruda, Adriano Cleis, Perilhão, Mauro Sérgio, Santos, Warley Almeida, Gregnani, Marcos Fernandes, Budu, Alexandre, Neto, José Cesar Rosa, Estrela, Gabriel Rufino, Araujo, Ronaldo Carvalho
Format: Article
Language:English
Subjects:
Antidiabetics
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Drugs
Gemfibrozil
Gene expression
kidney
Kidneys
Kinases
mate-1
Metformin
oct-2
Pharmacodynamics
Pharmacokinetics
Pharmacovigilance
Phosphorylation
pparα
transcription
Transcription factors
Urine
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25020392