Polymyxin B exerts nephrotoxicity effects via inhibition of the Nrf2/NQO1 pathway‐mediated antioxidant response

Author:

Xiao Guiying123,Yuan Fang12,Deng Yang12,Xiang Debiao12,Xiong Liguang123,Li Xin123ORCID,Li Yuan12

Affiliation:

1. Department of Pharmacy The Third Hospital of Changsha Changsha Hunan China

2. Institute of Clinical Application of Antibiotics The Third Hospital of Changsha Changsha Hunan China

3. Department of Pharmacy, The Third Hospital of Changsha Hunan University of Chinese Medicine Changsha Hunan China

Abstract

AbstractPolymyxin B (PMB) is a polypeptide antibiotic widely used in treating multidrug‐resistant Gram‐negative bacteria. However, nephrotoxicity is a serious adverse effect that limits its clinical use. Therefore, clarification of the molecular mechanism of PMB‐induced renal injury is essential. Our study aimed to explore possible mechanisms of PMB‐induced nephrotoxicity in vivo and in vitro. Mice were treated with PMB to construct the kidney injury model. The antioxidant capacity was assessed by measuring the superoxide dismutase (SOD) and catalase (CAT) activities and the glutathione (GSH) and malondialdehyde (MDA) contents. The pathway of the nuclear factor erythroid 2‐related factor 2/NADH quinone oxidoreductase 1 (Nrf2/NQO1) was examined after PMB treatment in NRK‐52E cells and mice. Finally, the expressions of genes and proteins (Bax, Bcl‐2, Caspase‐3, Caspase‐9) related to apoptosis were evaluated through quantitative polymerase chain reaction and western blot assay. The study verified PMB‐induced nephrotoxicity in mice and NRK‐52E cells in a dose‐ and time‐dependent manner. PMB treatment significantly decreased the expression of Nrf2 and its downstream target gene NQO1 and increased the apoptosis‐related proteins expression. In summary, our results suggested that PMB‐induced oxidative stress damage by inhibiting the Nrf2/NQO1 pathway and promoting apoptosis in kidney tissues.

Funder

Hunan Provincial Science and Technology Department

Publisher

Wiley

Subject

Health, Toxicology and Mutagenesis,Toxicology,Molecular Biology,Molecular Medicine,Biochemistry,General Medicine

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