Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury

Mizuno, Tomohiro; Sato, Waichi; Ishikawa, Kazuhiro; Terao, Yuki; Takahashi, Kazuo; Noda, Yukihiro; Nagamatsu, Tadashi

doi:10.2147/ott.s86743

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…Indeed, we found that the administration of cisplatin to MATE1-deficient mice was associated with increases in several commonly used biomarkers of drug-induced acute kidney injury, including blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) compared with the values observed in wild-type mice (Supplemental Figure S1). These findings are consistent with prior observations in similar geneticallyengineered mouse models [54][55][56] or studies involving the administration of cisplatin together with inhibitors of MATE1 [57,58], and are in line with observations made in patients receiving treatment with cisplatin who carry impaired function variants in SLC47A1, the gene that encodes MATE1 [59][60][61].…”

Section: Modulation Of Oxaliplatin Pharmacokinetics By Tki Treatmentsupporting

confidence: 92%

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

et al. 2021

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The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.

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Section: Modulation Of Oxaliplatin Pharmacokinetics By Tki Treatmentsupporting

confidence: 92%

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

et al. 2021

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“…Tubular injury is a key pathology associated with the nephrotoxic effects of cisplatin. Tubular injury promotes reduced GFR and therefore delayed urinary excretion of cisplatin, leading to platinum accumulation within the tubules [ 83 ]. Given the pathogenesis linked to platinum accumulation in PTEC, increasing the expression of cisplatin efflux transporters has been a molecular target against CIAKI.…”

Section: Pharmacological Approaches Targeting Cisplatin Cellular Ementioning

confidence: 99%

“…It is possible that an increase in MRP expression might be seen in models of nephrotoxicity; however, no studies are yet to present data investigating this. In addition to MRPs, multi-antimicrobial extrusion protein 1 (MATE1/SLC47A1) is suggested to be involved in platinum accumulation associated with cisplatin treatment [ 83 ].…”

Section: Pharmacological Approaches Targeting Cisplatin Cellular Ementioning

confidence: 99%

“…MATE1 expression is largely concentrated in the brush-border membrane of PTECs and assists epithelial cell elimination of cationic molecules into urine [ 83 ]. Cisplatin has been identified as a substrate for MATE1 [ 90 ].…”

Section: Pharmacological Approaches Targeting Cisplatin Cellular Ementioning

confidence: 99%

“…MATE1 has shown to mediate cisplatin efflux and prevent cisplatin accumulation in tubular cells preventing cisplatin nephrotoxic effects [ 65 ]. However, following cisplatin treatment, downregulation of MATE1 expression in human tubular epithelial cells is observed [ 83 ]. Given the ability for MATE1 to facilitate cisplatin urinary excretion, further investigations have been undertaken to isolate its role in cisplatin-induced AKI.…”

Section: Pharmacological Approaches Targeting Cisplatin Cellular Ementioning

confidence: 99%

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Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations

McSweeney

Gadanec

Qaradakhi

et al. 2021

Cancers

216

134

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Administration of the chemotherapeutic agent cisplatin leads to acute kidney injury (AKI). Cisplatin-induced AKI (CIAKI) has a complex pathophysiological map, which has been linked to cellular uptake and efflux, apoptosis, vascular injury, oxidative and endoplasmic reticulum stress, and inflammation. Despite research efforts, pharmaceutical interventions, and clinical trials spanning over several decades, a consistent and stable pharmacological treatment option to reduce AKI in patients receiving cisplatin remains unavailable. This has been predominately linked to the incomplete understanding of CIAKI pathophysiology and molecular mechanisms involved. Herein, we detail the extensively known pathophysiology of cisplatin-induced nephrotoxicity that manifests and the variety of pharmacological and genetic alteration studies that target them.

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Regulation of renal organic cation transporters

Pernecker,

Ciarimboli

2024

FEBS Letters

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Transporters for organic cations (OCs) facilitate exchange of positively charged molecules through the plasma membrane. Substrates for these transporters encompass neurotransmitters, metabolic byproducts, drugs, and xenobiotics. Consequently, these transporters actively contribute to the regulation of neurotransmission, cellular penetration and elimination process for metabolic products, drugs, and xenobiotics. Therefore, these transporters have significant physiological, pharmacological, and toxicological implications. In cells of renal proximal tubules, the vectorial secretion pathways for OCs involve expression of organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) on basolateral and apical membrane domains, respectively. This review provides an overview of documented regulatory mechanisms governing OCTs and MATEs. Additionally, regulation of these transporters under various pathological conditions is summarized. The expression and functionality of OCTs and MATEs are subject to diverse pre‐ and post‐translational modifications, providing insights into their regulation in various pathological conditions. Typically, in diseases, downregulation of transporter expression is observed, probably as a protective mechanism to prevent additional damage to kidney tissue. This regulation may be attributed to the intricate network of modifications these transporters undergo, shedding light on their dynamic responses in pathological contexts.

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Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury

Cited by 8 publications

References 32 publications

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

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

Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations

Regulation of renal organic cation transporters

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