Abstract
Colistin has been considered as the last line of defense against Gram-negative bacterial infections, however, the potential nephrotoxicity limited its clinical use. 7-Hydroxycoumarin (7-HC) possesses many beneficial pharmacological activities. This study aimed to investigate the nephroprotective effects of 7-HC against colistin-induced kidney injury. In vivo experiments showed that 7-HC alleviated kidney injury induced by colistin, as indicated by lower levels of serum neutrophil gelatinase-associated lipocalin, blood urea nitrogen and creatinine levels. Both in vivo and in vitro results demonstrated that 7-HC alleviated oxidative stress and apoptosis induced by colistin, as shown by decreased malondialdehyde levels, decreased caspase-3 and caspase-9 activities, and increased superoxide dismutase and catalase activities. We also found that colistin significantly induced histone deacetylase (HDAC) 1 expression that deacetylated histone 3 at Lys27 acetylation (H3K27AC) of Nrf2 promoter region and hence inhibiting Nrf2 signaling. 7-HC treatment restored histone acetylation at the Nrf2 promoter region and hence promoted Nrf2 expression. These results suggested that 7-HC alleviates colistin-induced renal injury and this effect was achieved by enhancement of renal antioxidant capacity with the decreased level of HDAC1 and the activation of Nrf2 signaling pathway.
Highlights
In the past 20 years, there has been a pronounced increase in the emergence of multiple resistance of Gram-negative bacterial infections, especially multiresistant Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa (Lachiewicz et al, 2017; Tissera et al, 2017)
We demonstrate that 7-HC is an effective nephroprotective agent against colistin-induced kidney injury and the protective effect was achieved through the decreased level of HDAC1 and the activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway
We found that HDAC1binds to Nrf2 promoter region in Mouse renal tubular epithelial cells (mRTECs) and this binding increased significantly after colistin treatment. 7-HC treatment could reduce the expression of HDAC1, thereby reducing the binding between HDAC1 and Nrf2 promoter region (Figure 6A, all P < 0.01)
Summary
In the past 20 years, there has been a pronounced increase in the emergence of multiple resistance of Gram-negative bacterial infections, especially multiresistant Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa (Lachiewicz et al, 2017; Tissera et al, 2017). It is necessary to develop effective nephroprotective agents for optimizing clinical use of colistin. Understanding the mechanism of colistin-induced kidney injury is crucial for the development of nephroprotective agents. Colistin-induced kidney injury is characterized by increased generation of reactive oxygen species (ROS), which results in oxidative stress and apoptosis (Dai et al, 2015; Dai et al, 2017). Sirtuin 7, a member of HDACs, knockout ameliorates cisplatin-induced acute kidney injury through regulating the nuclear expression of transcription factor NF-kB that resulted in decreased TNFa expression (Yoshikazu et al, 2018). Clarifying the role of HDAC in colistin-induced kidney injury and targeting HDAC may contribute to develop effective nephroprotective agents against colistin-induced kidney injury
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