Abstract
Acute kidney injury (AKI) is a common syndrome which is strongly linked to high morbidity and mortality. Hypoxia is the leading cause of AKI and the proximal renal tubular cells are the most damaged part in the kidney during this period. It has been observed that 7,8-dihydroxyflavone (7,8-DHF) plays a protective role by acting on antiapoptosis and antioxidative stress. In this study we explored functions of 7,8-DHF in protecting human proximal tubular cell line HK-2 from hypoxia insults. We observed that treatment of 7,8-DHF could improve the viability of ischemic cell. Mechanistically, we found that 7,8-DHF could elevate the expression of cysteine-rich protein 61 (Cyr61), a protective immediate early gene in AKI. In addition, treatment of 7,8-DHF decreased CCAAT/enhancer-binding protein homologous protein (CHOP) expression, which is a marker protein during endoplasmic reticulum (ER) stress activation. Intriguingly, overexpression of Cyr61 significantly reduced CHOP expression. Taken together, our results provide novel insights into the possible protective role of 7,8-DHF by activating Cyr61 signaling and suppressing ER stress in hypoxic HK-2 cells which have potential clinical implications for the treatment of AKI.
Highlights
There has been a gradually increasing mortality and morbidity of acute kidney injury (AKI) worldwide [1]
We found that hypoxia induced the unfolded protein response (UPR) as revealed by elevated mRNA expression of the glucose-regulated protein 78 (GRP78)
Our results showed that under hypoxia condition CCAAT/enhancer-binding protein homologous protein (CHOP) mRNA expression was decreased upon 7,8-DHF treatment (Figure 5(a)) whereas there was no obvious change for other endoplasmic reticulum (ER) stress molecules (Figures 5(b), 5(c), and 5(d))
Summary
There has been a gradually increasing mortality and morbidity of acute kidney injury (AKI) worldwide [1]. Numerous evidences have been reported that 7,8-DHF produces pivotal biological functions mainly through activating TrkB receptors. It plays an important role in promoting neuron regeneration in some neurodegenerative diseases, BioMed Research International such as Alzheimer’s disease and Parkinson’s [11,12,13]. Treatment with 7,8-DHF protects retinal ganglion cells from excitotoxic and oxidative stress-induced apoptosis and cell death [18]. Our study indicated the hypoxia induced HK-2 protective property of 7,8-DHF by controlling Cyr and ER stress signaling, which may provide a novel therapeutic strategy of AKI
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