Transplantation/immunology
Celastrol protects kidney against ischemia–reperfusion-induced injury in rats

https://doi.org/10.1016/j.jss.2013.07.048Get rights and content

Abstract

Background

Ischemia–reperfusion (IR) causes various damages in renal tissues, which is exacerbated by hypoxia-induced excessive inflammation and deteriorates the prognosis of patients after kidney surgery. Celastrol is a potent inflammation inhibitor that has little toxicity. In this report, we investigated whether celastrol protects against IR-induced renal injury in rats.

Materials and methods

Renal IR injury was induced by occlusion of the bilateral renal pedicles for 45 min followed by reperfusion for 6 h. Celastrol or vehicle solution was intraperitoneally injected 30 min before renal ischemia, respectively. Renal histology, function, and pro-inflammatory cytokines and mediators were assessed. The effect of celastrol on nuclear translocation of nuclear factor kappa B (NF-κB) was also measured.

Results

Celastrol significantly suppressed elevation of the renal function markers and the lipid peroxidation level, alleviated renal tubular damage, and decreased the levels of tumor necrosis factor-α, interleukin-1β, and monocyte chemotactic protein-1 (MCP-1) messenger RNA in kidney caused by IR. Moreover, celastrol prevented IR-induced expression of pro-inflammatory mediators, which was associated with suppression of nuclear translocation of NF-κB subunit p65.

Conclusions

Celastrol ameliorated the acute kidney injury caused by IR, which was associated with inhibiting local NF-κB activation and inflammation. Our findings suggest that celastrol could be useful for preventing IR-induced renal injury.

Introduction

Ischemia–reperfusion (IR)-induced renal injury, which occurs in various clinical conditions such as kidney transplantation, kidney vascular surgery, cardiac failure, and shock resuscitation [1], [2], [3], is one of the main reasons of acute renal failure and a serious health problem of both society and patients [4]. Recent studies have identified a variety of pharmaceuticals including erythropoietin [5], propofol [6], and glutamine [7] for treating renal IR injury. However, the efficacy of these existing treatments for IR-induced renal injury is still limited and few renal protectants have been successfully translated into clinical application. Therefore, there is an urgent need for developing effective drugs for treating IR-induced renal injury.

Renal damage starts immediately after the onset of ischemia because of dramatic decrease in oxygen and nutrition in the renal tissues. To restore renal blood perfusion in the earliest time is critical to reduce renal injury. However, a large number of animal and clinical studies indicate that the subsequent reperfusion would worsen cell metabolic disorders and lead to additional damages in renal structure and function [8]. The mechanisms of renal IR injury include infiltration of inflammatory cell [9], generation of inflammatory factors such as cytokines, chemokines and, other pro-inflammatory mediator [10], and accumulation of free oxygen radicals [11]. It is also demonstrated that IR aggravates renal structural damages including tubular dilatation, congestion, brush border loss, and epithelial cell necrosis [5].

Celastrol, also known as tripterine, is an active ingredient of Chinese medicine Tripterygium wilfordii. In China, the extract of T wilfordii has been widely used in treating autoimmune diseases and chronic nephritis. Because of its anti-inflammatory and antioxidative activity, celastrol is a potent agent for treating inflammatory disorders including arthritis, asthma, Crohn's disease, and Parkinson's disease [12]. Moreover, celastrol has been found to have an anticancer activity against prostate cancer and breast cancer [13], [14]. Recently, it has been proven that celastrol can protect cerebral ischemic injury and reduce brain infarct volume as well as water content in a rat stroke model [15]. However, little is known if celastrol is able to protect kidney against IR-induced injury.

In this study, we investigated the effect of celastrol on IR-induced renal injury in a rat model and the underlying mechanism of this effect. The results suggest that celastrol could be used for preventing IR-induced renal injury.

Section snippets

Celastrol and animal

Celastrol (>99% pure) was purchased from Paypay Technologies, Inc. (Shenzhen, China), dissolved in 0.9% sodium chloride (NaCl) containing 1% dimethyl sulfoxide at a concentration of 1 mg/mL, and stored at −20°C.

Adult male Sprague-Dawley rats (250–280 g) were obtained from the Laboratory Animal Center of Chongqing Medical University. The animal procedures were in accordance with the Institutional Animal Care and Use Committee of Chongqing Medical University. All rats used in this study were free

Celastrol attenuated renal injury after renal IR in rats

To investigate the protective effect of celastrol on renal dysfunction caused by IR injury, plasma Cr and BUN levels at 6 h after renal reperfusion were measured (Fig. 1A and B). Compared with the sham group, rats that underwent renal IR exhibited a significant increase in concentration in both Cr and BUN (P < 0.01). However, celastrol significantly decreased the levels of Cr and BUN induced by renal IR injury in a dose-dependent manner (P < 0.05).

Next, kidney tissues collected at 6 h after

Discussion

To our knowledge, the present study is the first to investigate the effect of celastrol on IR-induced renal injury in a rat model. Pretreatment with celastrol prevented renal dysfunction and attenuated renal tubular damage, and reduced the inflammatory response at the early stage of renal IR, suggesting that celastrol was able to protect against renal injury induced by IR in rats.

Celastrol is one of the bioactive components derived from the Chinese herb T wilfordii, which has been used for the

Acknowledgment

The authors would like to thank Junlin He, Xuemei Chen, and Xueqing Liu of the research group at the Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University for their support and advice, and Shangjing Liu for the technical support.

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