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

• Published in: International journal of molecular sciences 2020-10, Vol.21 (19), p.7416
• Main Authors: Freitas-Lima, Leandro Ceotto, Budu, Alexandre, Arruda, Adriano Cleis, Perilhão, Mauro Sérgio, Barrera-Chimal, Jonatan, Araujo, Ronaldo Carvalho, Estrela, Gabriel Rufino
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Antineoplastic Agents - adverse effects; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Binding sites; Biomarkers; Cations; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Creatinine; Cytokines; Down-regulation; Down-Regulation - drug effects; Extrusion; Glucose metabolism; Homeostasis; Inflammation; Kidney - drug effects; Kidney - metabolism; Kidneys; Lipid metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Organic Cation Transporter 2 - genetics; Organic Cation Transporter 2 - metabolism; Peroxisome proliferator-activated receptors; PPAR alpha - genetics; PPAR alpha - metabolism; Proteins; Proximal tubules; Renal function; Renal Insufficiency - chemically induced; Renal Insufficiency - metabolism; Rodents; Severity of Illness Index; Signal Transduction - drug effects; Signal Transduction - genetics; Solid tumors; Toxicity; Transcription factors; Urine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21197416

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