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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

PPAR-alpha Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2

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Autor(es):
Freitas-Lima, Leandro Ceotto [1] ; Budu, Alexandre [1] ; Arruda, Adriano Cleis [1, 2] ; Perilhao, Mauro Sergio [1, 2] ; Barrera-Chimal, Jonatan [3, 4] ; Araujo, Ronaldo Carvalho [1, 2] ; Estrela, Gabriel Rufino [2, 5]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo, Dept Biofis, BR-04039032 Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Dept Med, Disciplina Nefrol, BR-04039032 Sao Paulo - Brazil
[3] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 04510, DF - Mexico
[4] Inst Nacl Cardiol Ignacio Chavez, Unidad Invest UNAM INC, Mexico City 14080, DF - Mexico
[5] Univ Fed Sao Paulo, Dept Oncol Clin & Expt, Disciplina Hematol & Hematoterapia, BR-04037002 Sao Paulo - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 19 OCT 2020.
Citações Web of Science: 0
Resumo

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-alpha) 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-alpha 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-alpha deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-alpha deletion restored the expression of these transporters. In addition, PPAR-alpha knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-alpha deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2. (AU)

Processo FAPESP: 17/23599-6 - Receptores de cininas e imunometabolismo
Beneficiário:Leandro Ceotto Freitas Lima
Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
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