Organic anion transporters 1 (OAT1) and OAT3 meditated the protective effect of rhein on methotrexate-induced nephrotoxicity

Liu, Zhihao; Jia, Yongming; Wang, Changyuan; Meng, Qiang; Huo, Xiaokui; Sun, Huijun; Sun, Pengyuan; Yang, Xiaobo; Ma, Xiaodong; Peng, Jinyong; Liu, Kexin

doi:10.1039/c7ra02968c

Cited by 10 publications

(9 citation statements)

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“…Recently, a case control study revealed that patients with chronic kidney disease (CKD) had a higher frequency of the single nucleotide polymorphism (SNP) (−475T>T/G) which induced OAT1 expression, resulting in increased transportation of organic anion toxins into cells and increased risk of CKD 21 . In our previous studies, OAT inhibitors (puerarin, resveratrol and rhein) decrease methotrexate renal toxicity in rats and cytotoxicity in human OAT1/3 (hOAT1/3) overexpressed cells through inhibiting the function of rat OATs (rOATs) and hOAT1/322., 23., 24.. Therefore, OAT1/3 plays a critical role in kidney injury by mediating accumulation of organic anionic toxins in the kidney.…”

Section: Introductionmentioning

confidence: 99%

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)

Huo

Meng

Wang

et al. 2019

Acta Pharmaceutica Sinica B

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Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.

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Section: Introductionmentioning

confidence: 99%

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)

Huo

Meng

Wang

et al. 2019

Acta Pharmaceutica Sinica B

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“…Human-derived cell lines including HEK293 can acquire resistance to MTX through the several fold amplification of dhfr; [17][18][19] in addition, their halfmaximal inhibitory concentration (IC 50 ) of MTX is approximately 100 nM. [20][21][22] Like HEK293 cells, the transfected WT-HEK cell pool showed no growth suppression up to 10 nM MTX. The endogenous dhfr copy number in the transfected WT-HEK cell pool almost doubled at 10 nM MTX (Figure S7).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of dihydrofolate reductase‐mediated gene amplification for the establishment of recombinant human embryonic kidney 293 cells producing monoclonal antibodies

Lee

Baek

Lee

2020

Biotechnology Journal

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Human embryonic kidney 293 (HEK293) cells with glycosylation machinery have emerged as an alternative host cell line for stable expression of therapeutic glycoproteins. To characterize dihydrofolate reductase/methotrexate (DHFR/MTX)-mediated gene amplification in HEK293 cells, an expression vector containing dhfr and monoclonal antibody (mAb) gene was transfected into dhfr-deficient HEK293 cells generated by knocking out dhfr and dhfrl1 in HEK293E cells. Due to the improved selection stringency, mAb-producing parental cell pools could be generated in the absence of MTX. When subjected to stepwise selection for increasing MTX concentrations such as 1, 10, and 100 nM, there was an increase in the specific mAb productivity (q mAb ) of the parental cell pool upon DHFR/MTX-mediated gene amplification. High producing (HP) clones with a q mAb of more than 2-fold of the corresponding cell pool could be obtained using the limiting dilution method. The q mAb of most HP clones obtained from cell pools at elevated MTX concentrations significantly decreased during longterm culture (3 months) in the absence of selection pressure. However, some HP clones could maintain high q mAb during long-term culture. Taken together, a stable HP recombinant HEK293 cell line can be established using DHFR/MTX-mediated gene amplification together with dhfr − HEK293 host cells.

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“…Furthermore, flavonoids and anthraquinones possessed renal protective effects. In our previous studies, puerarin and rhein ameliorated rat AKI induced by methotrexate through inhibition of renal OAT (Liu et al, 2014;Liu, Jia, et al, 2017). Considering that OAT inhibition and renal protection by rhein had been fully understood, we focused on Apigenin in the present study.…”

Section: Development Of Apigenin As Oats Inhibitormentioning

confidence: 99%

“…To identify and optimize the active ingredient in TCM has been an important strategy for the modernization of TCM and drug discovery and development in China (Hon & Lee, 2017). In our previous studies, natural products like puerarin, resveratrol, and rhein reduced the renal toxicity induced by methotrexate in rats by inhibition of renal Oats (Jia et al, 2016;Liu et al, 2014;Liu, Jia, et al, 2017). Moreover, it was reported that natural flavonoid morin exhibited protective effect against Imp-induced nephrotoxicity in rabbits, the mechanism which might be related to OAT3-mediated renal excretion of Imp (Lim et al, 2008).…”

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confidence: 99%

Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem‐induced nephrotoxicity

Huo

Meng

Wang

et al. 2020

Phytotherapy Research

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Imipenem (Imp) is a widely used broad-spectrum antibiotic. However, renal adverse effects limit its clinical application. We previously reported that organic anion transporters (OATs) facilitated the renal transport of Imp and contributed its nephrotoxicity. Natural flavonoids exhibited renal protective effect. Here, we aimed to develop potent OAT inhibitors from traditional Chinese medicines (TCMs) and to evaluate its protective effect against Imp-induced nephrotoxicity. Among 50 TCMs, Tribuli Fructus, Platycladi Cacumen, and Lycopi Herba exhibited potent inhibition on OAT1/3. After screening their main components, Apigenin strongly inhibited Imp uptake by OAT1/3-HEK293 cells with IC50 values of 1.98 ± 0.36 μM (OAT1) and 2.29 ± 0.88 μM (OAT3). Moreover, Imp exhibited OAT1/3-dependent cytotoxicity, which was alleviated by Apigenin. Furthermore, Apigenin ameliorated Imp-induced nephrotoxicity in rabbits, and reduced the renal secretion of Imp. Apigenin inhibited intracellular accumulation of Imp and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells (rPTCs). Apigenin, a flavone widely distributed in TCMs, was a potent OAT1/3 inhibitor. Through OAT inhibition, at least in part, Apigenin decreased the renal exposure of Imp and consequently protected against the nephrotoxicity of Imp. Apigenin can be used as a promising agent to reduce the renal adverse reaction of Imp in clinic.

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Organic anion transporters 1 (OAT1) and OAT3 meditated the protective effect of rhein on methotrexate-induced nephrotoxicity

Abstract: Rhein protects methotrexate induced kidney damage mediated by OAT1 and OAT3.

Cited by 10 publications

References 40 publications

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)

Comprehensive characterization of dihydrofolate reductase‐mediated gene amplification for the establishment of recombinant human embryonic kidney 293 cells producing monoclonal antibodies

Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem‐induced nephrotoxicity

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