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

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-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.

In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors

“…It is noteworthy that the same pattern of inhibition was observed for An alternative route by which TKIs affect MATE1 function is through effects on transcription factors that result in gene expression changes. Previous studies have suggested a possible role for PPARα [36,37], and basal transcription of the MATE1 gene is regulated by FXR [38] and by binding of Sp1 close to the transcription start site [39], by binding of AP-1/AP2-rep to the promoter region [40], and by Nkx-2.5, SREBF1, and USF-1 [41].…”

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

“…Cisplatin mouse models have been used to investigate pharmacokinetics and tissue distribution of cisplatin [15][16][17], the repair capacity of cisplatin-DNA adducts [18], the molecular mechanisms of cisplatin toxicity [19][20][21][22][23] and to test a new generation of platinumbased chemotherapy drugs or adjunctive therapies [24][25][26][27][28][29][30][31][32][33][34][35], or other potential agents or strategies to prevent or treat cisplatin toxicities [36][37][38][39][40][41].…”

Glucose Metabolism in Acute Kidney Injury and Kidney Repair

“…Cisplatin is a powerful antineoplastic agent that may induce nephrotoxicity. It causes tubular injury and cell death through multiple mechanisms, including DNA damage, oxidative stress, mitochondrial dysfunction, and inflammation ( 81 , 82 ). Impairment of glucose metabolism has been implicated in cisplatin-induced AKI.…”