Targeting HO-1 by Epigallocatechin-3-Gallate Reduces Contrast-Induced Renal Injury via Anti-Oxidative Stress and Anti-Inflammation Pathways.

Zhao Gao,Jinjuan Fu,Xiaoqun Zhang,Chunyu Zeng,Yunhui Hu,Yongbin Wang,Xiongwen Chen,Xi Lu,Yu Han,Jun Zhang,Xue Zou,Pedro A Jose,Xiaoyan Wu,Cecilia Zazueta

doi:10.1371/journal.pone.0149032

Zhao Gao, Jinjuan Fu + Show 12 more

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https://doi.org/10.1371/journal.pone.0149032

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Abstract

Both oxidative stress and inflammation are involved in the pathogenesis of contrast-induced nephropathy (CIN). Epigallocatechin-3-gallate (EGCG), a purified catechin from green tea, has antioxidant and anti-inflammatory effects. However, it is unknown whether or not EGCG is effective in treating CIN. Our present study found that intravenous administration of EGCG, either before or just after the establishment of CIN, had a protective effect, determined by normalization of serum creatinine and blood urea nitrogen levels, improvement in renal histopathological scoring and alleviation of apoptosis, accompanied by decreased oxidative stress and inflammation. Because EGCG is a potent inducer of the antioxidant heme oxygenase-1 (HO-1), we studied HO-1 signaling in CIN. HO-1 levels were increased in CIN; treatment with EGCG further increased HO-1 levels, accompanied by an increase in Nrf2, a regulator of antioxidant proteins. Interestingly, blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) prevented the protective effect of EGCG on CIN. ZnPP also blocked the ability of EGCG to increase the activity of an antioxidant (superoxide dismutase), and decrease markers of oxidative stress (myeloperoxidase and malondialdehyde) and inflammation (myeloperoxidase and IL-1β), indicating that HO-1 is the upstream molecule that regulates the EGCG-mediated protection. To determine further the role of HO-1 on the EGCG-mediated inhibition of inflammation, we studied the effect of EGCG on the NLRP3 inflammasome, an upstream signaling of IL-1β. EGCG down-regulated NLRP3 expression, which was blocked by ZnPP, indicating that HO-1 links EGCG with NLRP3. Therefore, EGCG, via up-regulation of HO-1, protects against CIN by amelioration of oxidative stress and inflammation.

Highlights

Contrast-induced nephropathy (CIN) continues to be a common iatrogenic cause of acute kidney injury (AKI) after exposure to iodinated contrast medium (CM), e.g., during percutaneous coronary intervention (PCI), despite the tailored preventive strategies that include risk stratification for the individual patient, hydration, newer and safer CM and additional preventive methods (e.g., N-acetylcysteine [1], sodium bicarbonate [2], fenoldopam [3], statins [4,5], limb ischemic preconditioning [6], and preemptive hemodialysis [7])
We found that the beneficial effect of EGCG in a CIN rat model involved an EGCG-mediated up-regulation of heme oxygenase-1 (HO-1) that mitigated both oxidative stress and inflammation
Intravenous pretreatment with 5 to 20mg/kg body wt of EGCG was able to reduce the extent of CIN, as assessed by renal function markers, i.e., serum Cr, blood urea nitrogen (BUN), and creatinine clearance (CrCl) at 24h after the injury (Fig 1C–1E)

Summary

Introduction

Contrast-induced nephropathy (CIN) continues to be a common iatrogenic cause of acute kidney injury (AKI) after exposure to iodinated contrast medium (CM), e.g., during percutaneous coronary intervention (PCI), despite the tailored preventive strategies that include risk stratification for the individual patient, hydration, newer and safer CM and additional preventive methods (e.g., N-acetylcysteine [1], sodium bicarbonate [2], fenoldopam [3], statins [4,5], limb ischemic preconditioning [6], and preemptive hemodialysis [7]). Oxidative stress and inflammation have been implicated in the pathogenesis of CIN [8,9]. CM filtered by the glomerulus, actively taken up by renal tubular cells and retained within the cells and peritubular space, especially in patients with chronic kidney impairment, has a direct toxic action on tubular cells, increasing oxygen consumption, and induces vasoconstriction of the vasa recta, decreasing oxygen delivery, inducing a state of hypoxia. CM triggers a series of reactions that lead to the release of free radicals, causing cellular damage and initiating the vicious cycle of oxidative stress and inflammation. A possible treatment strategy could involve the use of medications that target the regulators of both renal oxydative stress and inflammation

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