Transplantation/immunology
Penehyclidine hydrochloride ameliorates renal ischemia–reperfusion injury in rats

https://doi.org/10.1016/j.jss.2013.07.041Get rights and content

Abstract

Background

Renal ischemia–reperfusion (I/R) injury is a major cause of acute kidney failure by mechanisms that involve oxidative stress, inflammation, and apoptosis. Penehyclidine hydrochloride (PHC), a selective anticholinergic agent, possesses anti-inflammatory, antioxidative stress, and antiapoptotic effects. Therefore, we investigated the ability of PHC to ameliorate renal I/R injury in Sprague–Dawley rats.

Materials and methods

Rats were randomly assigned to three groups (35 rats per group): sham operated, saline-treated I/R, and PHC-treated I/R. After removing the right kidney, renal I/R injury was induced by clamping the left renal artery for 45 min followed by reperfusion. The rats were administered PHC (0.45 mg/kg, intravenously) or saline 30 min before renal ischemia. The blood and kidneys were harvested at 1, 3, 6, 12, or 24 h after reperfusion. Renal function and histologic changes were assessed. Markers of oxidative stress, inflammation, and apoptosis in the kidneys were also measured.

Results

PHC treatment significantly attenuated renal dysfunction and histologic damage caused by I/R injury. The treatment also decreased malondialdehyde level and attenuated the reduction in superoxide dismutase activity in the kidney. Moreover, the levels of activated p38 mitogen-activated protein kinase, nuclear factor kappa B, and caspase 3 were lower in the PHC-treated animals.

Conclusions

PHC protected rat kidneys from I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis. Thus, PHC may represent a novel practical strategy for the treatment of renal I/R injury.

Introduction

Renal ischemia–reperfusion (I/R) injury is a complex pathophysiological process, which develops in diverse clinical situations, such as trauma, shock, sepsis, and various surgical procedures. Renal I/R injury is a major cause of acute kidney injury, a potentially life-threatening condition associated with high mortality and morbidity [1], [2]. The mechanisms underlying ischemic acute renal injury involve local elevations in proinflammatory chemokines and cytokines and alterations in tubule cell metabolism, leading to the generation of reactive oxygen species (ROS). Consequently, excess ROS production causes lipid peroxidation, DNA mutation, and initiation of apoptotic and necrotic cascades, resulting ultimately in cell death [3], [4], [5], [6], [7].

Penehyclidine hydrochloride (PHC)—3-(2-hydroxyl-2-cyclopentyl-2-phenyl-ethoxy) quinuclidine (Fig. 1) [8], [9]—is a selective anticholinergic agent, which was developed by the Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, People's Republic of China. It has been widely used as an anesthetic premedication and as a treatment for smooth muscle spasm [10], [11], [12]. Previous studies in animals have shown that PHC reduces inflammation [13], [14] and oxidative stress [13] and inhibits the p38 and extracellular signal–regulated kinase signaling pathways [15]. PHC also attenuated renal or gastrointestinal damage caused by bilateral hind limb I/R by suppressing the inflammatory response and the release of oxygen-free radicals [16], [17], [18]. More recently, PHC has been shown to attenuate cerebral I/R injury in rats [19]. However, its effect on renal I/R injury remains unknown. Thus, the aim of this study was to evaluate the effects of PHC on renal I/R injury in adult Sprague–Dawley rats and elucidate the underlying mechanisms.

Section snippets

Chemicals and reagent

PHC injection (1 mg/1 mL) was purchased from List Pharmaceutical (Chengdu, China).

Animal preparation and drug administration

Adult, male Sprague–Dawley rats (180–220 g) were provided by Laboratory Animal Center of Peking University Health Science Center. Rats were housed at 27°C and were given rodent chow and tap water ad libitum. All procedures were approved by the Ethics Committee of Experimental Animals of The Peking University Health Science Center and were performed in accordance with the Guide for the Care and Use of Laboratory

PHC ameliorates I/R-induced renal dysfunction

Compared with the sham controls, the I/R group showed significantly increased BUN and SCr levels after 1 h, and the levels peaked 24 h after reperfusion (P < 0.01). Pretreatment with PHC reduced BUN and SCr levels at all time points (P < 0.01) (Fig. 2).

PHC treatment decreases histopathologic damage to tubules

Compared with the normal tubular histology in the sham group, tubular dilatation, swelling, luminal congestion, and nuclear pyknosis were observed 3 and 12 h after renal reperfusion in the kidneys from the I/R group, and histopathology was even

Discussion

When the blood flow is interrupted, renal warm ischemia occurs. A hypoxic state ensues and causes the local accumulation of anaerobic metabolites and free radicals. Renal dysfunction and cellular degeneration occur in the renal tissue. After blood flow is restored, an oxidant burden occurs because of decrease of molecular oxygen and increase of hydrogen peroxide, which induces the majority of the damage to renal tissues. Renal tissue I/R induces the production of inflammatory factor, such as

Acknowledgment

This work was supported by the National Natural Science Foundation of China (grant 30950018) and the Beijing Natural Science Foundation (grant 7113174).

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