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


Journal

Phytotherapy research : PTR
ISSN: 1099-1573
Titre abrégé: Phytother Res
Pays: England
ID NLM: 8904486

Informations de publication

Date de publication:
Nov 2020
Historique:
received: 23 12 2019
revised: 11 04 2020
accepted: 25 04 2020
pubmed: 30 5 2020
medline: 12 1 2021
entrez: 30 5 2020
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 32468621
doi: 10.1002/ptr.6727
doi:

Substances chimiques

Organic Anion Transporters 0
Imipenem 71OTZ9ZE0A
Apigenin 7V515PI7F6

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2998-3010

Subventions

Organisme : National Natural Science Foundation of China
ID : 81874324
Organisme : National Natural Science Foundation of China
ID : 81903706
Organisme : National Natural Science Foundation of China
ID : U1608283
Organisme : Science and Technology Innovation Found
ID : 2018J12SN065

Informations de copyright

© 2020 John Wiley & Sons, Ltd.

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Auteurs

Xiaokui Huo (X)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.
Provincial Key Laboratory for Pharmacokinetics and Transport Liaoning, Dalian Medical University, Dalian, China.

Qiang Meng (Q)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.
Provincial Key Laboratory for Pharmacokinetics and Transport Liaoning, Dalian Medical University, Dalian, China.

Changyuan Wang (C)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.
Provincial Key Laboratory for Pharmacokinetics and Transport Liaoning, Dalian Medical University, Dalian, China.

Jingjing Wu (J)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.

Yanna Zhu (Y)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.

Pengyuan Sun (P)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.

Xiaodong Ma (X)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.

Huijun Sun (H)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.
Provincial Key Laboratory for Pharmacokinetics and Transport Liaoning, Dalian Medical University, Dalian, China.

Kexin Liu (K)

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.
Provincial Key Laboratory for Pharmacokinetics and Transport Liaoning, Dalian Medical University, Dalian, China.

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