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

Author(s)

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]}

Affiliation

^[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

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 19 OCT 2020.
• Web of Science Citations: 0

Abstract

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)

• 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