Abstract
Oxidative stress plays a critical role in the pathophysiology of contrast-induced nephropathy (CIN). Since the specific treatment of CIN remains an unmet medical need, it is imperative to find an effective strategy against the clinical management of CIN. The transcription factor Nrf2 is known to regulate antioxidative stress response. The aim of the present study was to assess the effects of tert-butylhydroquinone (t-BHQ), an activator of Nrf2, in the prevention of CIN and elucidate the underlying mechanism of its action in vitro and in vivo. We established a rat model of CIN and treated the animals with t-BHQ (25 mg/kg). The effects of t-BHQ treatment on CIN rats were elucidated by assessing renal function, HE staining, immunohistochemistry, and western blotting. We also studied the activity of oxidative stress-related markers, such as intracellular ROS level, MDA level, SOD2 activity, and GSH/GSSG ratio. We validated our results by siRNA-mediated silencing of Nrf2 in HK-2 cells exposed to the radiocontrast agent. Treatment with t-BHQ significantly ameliorated the renal function and the histopathological lesions in CIN rats. Further, pretreatment with t-BHQ significantly increased the SOD2 activity and GSH/GSSG ratio and decreased the levels of ROS and MDA in animals subjected to ioversol exposure. In addition, t-BHQ treatment increased the expression of Nrf2, Sirt3, and SOD2 and concomitantly decreased the expression of acetylated-SOD2. When Nrf2-silenced HK-2 cells were exposed to radiocontrast agent, they suffered severe cell oxidative stress, exhibited lower expression of Sirt3 and SOD2, and expressed higher levels of acetylated-SOD2; however, t-BHQ treatment did not affect the protein expression of these indicators in si-Nrf2 HK-2 cells. Our findings suggested that Nrf2 plays an important role in the regulation of the Sirt3/SOD2 antioxidative pathway, and t-BHQ may be a potential agent to ameliorate radiocontrast-induced nephropathy via activating the Nrf2/Sirt3/SOD2 signaling pathway in vitro and in vivo.
Highlights
Radiocontrast agents are widely used in invasive image examinations such as contrast-enhanced CT and angiography
The rats were anesthetized with pentobarbital sodium, and the following drugs were sequentially injected in the tail vein: indomethacin (Sigma, USA) (10 mg/kg), followed by Nw-nitro-L-arginine methyl ester (L-NAME) (Hengrui Medicine, Ltd., Jiangsu, China) (100 mg/kg) and ioversol (Hengrui Medicine, Ltd., Jiangsu, China) (2.9 g/kg) 15 and 30 min later
Our results showed that contrast agent exposure caused increase in intracellular reactive oxygen species (ROS) (Figure 3(a)); animals treated with ioversol showed lower SOD2 activity (Figure 3(c)) and GSH/GSSG ratio (Figure 3(d)) and a higher MDA content (Figure 3(b)) than the control group (P < 0:01)
Summary
Radiocontrast agents are widely used in invasive image examinations such as contrast-enhanced CT and angiography. Millions of patients who undergo radio imaging procedures are at the risk of contrast-induced nephropathy (CIN). In a meta-analysis of 29 studies where patients were injected with the radiocontrast medium either intravenously or intra-arterially, the incidence of CIN was observed to be between 4.4% and 22.1% [2]. CIN is defined as a rise in serum creatinine level ≥ 0:5 mg/dL or a ≥25% relative rise in creatinine level from baseline within 48 hours of exposure to the contrast agent, accompanied by an otherwise unexplained acute impairment in renal function [3]. Renal parenchymal hypoxia and the generation of reactive oxygen species (ROS) have been reported to play a critical role in the pathogenesis of CIN [4].
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