Fenofibrate Down-regulates Renal OCT2-mediated Organic Cation Transport via PPARα-independent Pathways

Abstract

Fibrate drugs, the peroxisome proliferator-activated receptor alpha (PPAR¡) agonists, are widely prescribed for the treatment of hyperlipidemia. The present study examined the effect of fibrate drugs on renal OCT2 activity in a heterologous cell system [Chinese hamster ovary (CHO-K1) cells stably transfected with rabbit (rb) OCT2], LLC-PK1, and intact mouse renal cortical slices. We found that both in the CHO-K1 cells expressing rbOCT2 and in LLC-PK1 cells, fenofibrate significantly inhibited [ 3 H]-MPP + uptake whereas clofibrate and WY14643 had no effect. Surprisingly, the inhibitory effect of fenofibrate was not attenuated by GW6471, a PPAR¡ antagonist, indicating that the inhibitory process observed was via a PPAR¡independent pathway. Fenofibrate decreased [ 3 H]-MPP + uptakes through a reduction of the maximal transport (J max) but without effect on the transporter affinity (K t) corresponding to a decrease in membrane expression of OCT2. Since the inhibitory effect of fenofibrate was not prevented by pretreatment with cycloheximide, its inhibitory action did not involve an inhibition of protein synthesis. Similar to the effect seen in the cell-cultured system, the inhibitory effect of fenofibrate was also observed in intact renal cortical slices. Taken together, our data showed that fenofibrate decreased the activity of OCT2 by reducing the number of functional transporters on the membrane, which is likely to be a PPAR¡-independent pathway.

Interaction of rosiglitazone and pioglitazone with organic cation transporters

“…The interactions of rosiglitazone with OCT1 and OCT2 found in heterologous expressing cell were verified in HepG2 cells and LLC-PK1 cells that endogenously express OCT1 and OCT2, respectively [20][21][22] . Our data demonstrated the similar inhibitory effect of rosiglitazone on organic cation transport in the endogenously expressing system of OCTs whereas pioglitazone produced no effect.…”

Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways

“…Potentially, cytotoxicity following high concentration cisplatin exposure was attenuated by fenofibrate but no other fibrates. As fenofibrate acts via a PPARα-independent mechanism (Asavapanumas et al, 2012;Wilk et al, 2015), checking whether the renoprotective effect of fenofibrate is mediated by PPARα activation was essential. Employing PPARα inhibition via a PPARα antagonist, GW6471, fenofibrate's protective effect was maintained, suggesting PPARα activation is not required.…”

Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population

“…Smoking withdrawal symptoms were also recorded by a self-administered questionnaire [20]. Each symptom was assessed by 3 or 4 questions and summarized with a score from a minimal to a maximal grade as follow: depression (min: 4 -max: 20), craving (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), irritation (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), concentration (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), appetite and weight gain (3)(4)…”

“…A variety of genetic polymorphisms of the SLC22A2 gene coding for the OCT2 transporter and of the UGT2B7 gene might have an influence on varenicline exposure. Expression of the genes coding for phase I and phase II drug-metabolizing enzymes and transporters, such as UGT2B7 and OCT2 are regulated by transcription factors such as: the constitutive androstane receptor (CAR, encoded by the NR1|3 gene), the pregnane X receptor (PXR, encoded by the NR1|2 gene), the estrogen receptor 1 (encoded by the ESR1 gene), the farnesoid X receptor (FXR, encoded by the NR1H4 gene), the peroxisome proliferator activated receptor gamma (PPARγ encoded by the NR1C2 gene) and its coactivator PPAR coactivator 1-alpha (PPARGC1A) which all have genetic polymorphisms [6][7][8][9][10][11][12][13][14].…”