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Annals of Clinical & Laboratory Science 36:326-332 (2006)
© 2006 Association of Clinical Scientists

An Angiotensin-Converting Enzyme Inhibitor, Zofenopril, Prevents Renal Ischemia/Reperfusion Injury in Rats

Bulent Altunoluk1, Haluk Soylemez2, Fatih Oguz2, Emine Turkmen3 and Ersin Fadillioglu4
1 Division of Urology, State Hospital of Kahramanmaras, Kaharamanmaras; 2 Departments of Urology and 3 Pathology, Faculty of Medicine, Inonu University, Malatya; and 4 Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara; Turkey

Address correspondence to Ersin Fadillioglu, M.D., Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; tel 90 312 305 1567; fax 90 312 310 0580; e-mail efadillioglu{at}yahoo.com.


   Abstract
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 Abstract
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 Materials and Methods
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Zofenopril ameliorates experimental cardiac ischemia/reperfusion (IR) injury in animal models and exhibits beneficial cardiovascular effects in patients with myocardial infarction. The objective of the present research was to investigate whether zofenopril can protect against renal IR injury. Rats were divided into 4 experimental groups: (a) control, (b) IR (60 min of ischemia followed by 24 hr of reperfusion), (c) zofenopril (15 mg/kg/day for 2 days), and (d) zofenopril+IR. All of the rats underwent right nephrectomy, and the rats in the IR and zofenopril+IR groups also underwent IR.then the left kidneys were removed for biochemical analyses and microscopic examination. There were no abnormalities in the biochemical and microscopic findings in the preoperative right kidneys. The lipid peroxidation, protein oxidation, and nitric oxide levels as well as xanthine oxidase and myeloperoxidase activities were increased and the catalase and superoxide dismutase activities were decreased in the IR group; zofenopril treatment prevented these changes (p <0.05). In the IR group, the kidney sections showed severe acute tubular damage including brush border loss, nuclear condensation, cytoplasmic swelling, and loss of nuclei; in the zofenopril+IR group, the normal glomerular morphology was preserved and there was slight edema of the tubular cells. The renal damage score was significantly reduced in the zofenopril+IR group vs the IR group (p <0.05).In conclusion, IR injury caused oxidative damage in renal tissue and zofenopril prevented this IR injury.

Keywords: zofenopril, kidney ischemia/reperfusion, oxidative stress, antioxidants


   Introduction
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 Introduction
Materials and Methods
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Cardiac and renal ischemia/reperfusion (IR) injury is a major clinical problem and several therapeutic strategies have been employed to reduce IR injury [1,2]. The process results in cellular injury triggering a complex series of biochemical events, which affect the structure and function of virtually every organelle and subcellular system of the affected cells [3]. Injury mediated by reactive oxygen species (ROS) can be expected to occur when the oxygen supplied to the tissue after an occlusion of circulation and ROS formation exceeds the cellular detoxification capacity of the tissue [4]. ATP production is diminished relative to the limited oxygen available during ischemia. During reperfusion of the tissue, molecular oxygen is consumed as an electron acceptor and used for formation of superoxide anion (O2·–) by xanthine oxidase (XO) [2,5]. Superoxide dismutase (SOD), one of the major intracellular antioxidant enzymes, rapidly and specifically reduces O2·– to H2O2. The other endogenous antioxidant enzyme, catalase (CAT), acts to detoxify H2O2 to water [6]. Free radicals, particularly reactive oxygen or nitrogen intermediates, are thought to be involved in inflammatory processes, exacerbating inflammation, and causing tissue damage [7]. Additionally, IR causes an acute inflammatory response characterized by activation of neutrophils that release myeloperoxidase (MPO), a multifunctional heme enzyme stored in azurophilic granules, into phagosomes and the extra-cellular space during the inflammatory process [8,9]. MPO catalyses the formation of hypochlorous acid (HOCl), which is toxic to cellular components and initiates oxidative injury [10]. Another inflammatory source for ROS is increased nitric oxide (NO) production during IR injury in tissues by activation of iNOS. NO interacts with superoxide anion to form a toxic product, peroxynitrite.

Zofenopril, a derivative of the amino acid proline and an inhibitor of angiotensin-converting enzyme (ACE) and angiotensin II [11], ameliorates experimental cardiac IR injury or doxorubicin-induced cardiac injury in animal models [12,13] and has beneficial cardiovascular effects in patients with myocardial infarction [14]. Mak et al [15] demonstrated that SH-containing ACE inhibitor agents, including zofenopril, can protect endothelial cells against free radical-induced lipid peroxidation and cell injury [15]. No study has yet been published on possible beneficial effects of zofenopril on renal oxidant injury. The goal of the present research was to test whether zofenopril can protect against renal IR injury.


   Materials and Methods
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 Materials and Methods
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Animals and experimental procedure.  The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (DHEW Publication No. 85–23, 1985) and were approved by the Ethics Committee of Inonu University School of Medicine. Female Sprague-Dawley rats were housed in a quiet room with 12:12-hr light-dark cycle (7 am to 7 pm). Rats were randomly assigned to one of four groups: (a) untreated control rats (n = 6); (b) IR-treated rats (n = 8); (c) zofenopril-treated rats (n = 6), and (d) zofenopril+IR-treated rats (n = 7). Zofenopril (Menarini Group, Italy) was given orally (15 mg/kg/day) for 2 days, starting 1 day before the experiment, to the zofenopril and zofenopril+IR groups.

On the day of experiment, rats were anesthetized with ketamine hydrocloride (75 mg/kg ip) and xylazine (8 mg/kg ip). The rats in all groups underwent right nephrectomy, and the right kidneys of the control rats were kept for analysis as preoperative control kidneys. After 10 min of stabilization, the left renal pedicle was occluded for 60 min to induce left renal ischemia, followed by 24 hr of reperfusion, in the IR and zofenopril+IR groups. At the end of the experiment, the left kidneys of all rats were removed and divided for microscopic and biochemical analyses. The tissues were stored -80°C until the biochemical analyses were performed.

Biochemical analyses.  After the kidneys were weighed, renal homogenate and supernatant samples were prepared as described elsewhere [4]. The chemicals for biochemical analyses were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Protein concentrations in homogenate and supernatant samples were assayed by the method of Lowry et al [16]. The activities of CAT [17], total (Cu-Zn and Mn) SOD [18], XO [19], and MPO [20] were analyzed spectrophoto-metrically as described. NO has a half-life of only a few sec, because it is readily oxidized to nitrite (NO2–) and nitrate (NO3–), which serve as index parameters of NO production. The method for tissue nitrite and nitrate levels was based on the Griess reaction [21]. Tissue malonyldialdehyde (MDA) level, an index of lipid peroxidation, was determined by a method [22] based on reaction with thiobarbituric acid (TBA) at 90–100°C. Tissue protein carbonyl content, an index of protein oxidation, was assayed by reaction of carbonyl groups with 2,4-dinitrophenylhydrazine to form 2,4-dinitrophenyl-hydrazone [23].

Histopathology.  Kidneys were fixed in 10% formalin, embedded in paraffin, sectioned at 5 µm, and stained with hematoxylin and eosin (H&E). Renal sections were examined by light microscopy and scored according to a semi-quantitative scale designed to evaluate the severity of renal damage. A score from 0 to 3 was given for each tubular profile involving an intersection: 0 = normal histology; 1 = tubular cell swelling, brush border loss, nuclear condensation, with less than one-third of the tubular profile showing nuclear loss; 2 = same as for score 1, but greater than one-third and less than two-thirds of the tubular profile showing nuclear loss; and 3 = greater than two-thirds of the tubular profile showing nuclear loss.

Statistics.  Data were analyzed using statistics software (SPSS for Windows, version 9.0). Distributions of the groups were analyzed with the one-sample Kolmogarov-Smirnov test. All groups showed normal distributions, so parametric statistical methods were used to analyze the data. One-way ANOVA was performed and post-hoc multiple comparisons were done with LSD. Results were expressed as mean ± SE; p values <0.05 were regarded as significant.


   Results
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Discussion
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Biochemical findings in renal tissue.  The results are listed in Table 1Go. There were no significant differ-ences in any biochemical parameters between the right kidney (preoperative) and the left kidney in the control group. Moreover, administration of zofenopril alone to rats did not alter any biochemical parameter.


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  		Table 1. The activities of catalase (CAT), superoxide dismutase (SOD), xanthine oxidase (XO), and myeloperoxidase (MPO), and the levels of malondialdehyde (MDA), nitric oxide (NO), and protein carbonyl content (PC) in renal tissue of control, ischemia/ reperfusion (IR), zofenopril-alone, zofenopril+IR, and preoperative control groups (mean ± SE).
 
The indices of lipid peroxidation and protein oxidation were increased by IR; the MDA level and protein carbonyl content of renal tissue in the IR group were significantly higher than the control group (p <0.05). Zofenopril treatment protected renal tissue from lipid peroxidation and protein oxidation; the MDA level and protein carbonyl content of renal tissue in the zofenopril+IR group were significantly lower than in the IR group (p <0.05). The activity of XO was increased in the IR group in comparison to the other groups (p <0.05) and zofenopril treatment attenuated this increase almost to the control level (p <0.05). MPO activity, produced by activated neutrophils, was significantly increased in the IR group in comparison with the control and zofenopril-alone groups (p <0.05) and zofenopril treatment prevented the IR-induced increase of MPO activity (p <0.05).

The activities of antioxidant enzymes, CAT and SOD, were lower in the IR group than the control groups (p <0.05) and zofenopril treatment increased the activity of CAT (but not SOD) almost to control levels (p <0.05). The level of NO in the IR group was significantly increased in comparison to other groups (p <0.05) and zofenopril treatment in the zofenopril+IR group attenuated this high NO level significantly (p <0.05).

Histopathologic findings in renal tissue.  Normal renal morphology was observed in the preoperative and postoperative control kidneys (Fig. 1AGo) as well as in the zofenopril-alone group (Fig. 1DGo). The sections of kidneys from animals that underwent renal IR demonstrated severe acute tubular damage including brush border loss, nuclear condensation, cytoplasmic swelling, and loss of significant numbers of nuclei from tubular profiles (Fig. 1BGo). In the zofenopril+IR group, the normal morphology of the kidney was preserved, with normal glomeruli and slight edema of tubular cells (Fig. 1CGo). The pathological damage score in the IR group (2.48 ± 0.19) was significantly higher than the zofenopril+IR group (1.25 ± 0.08; p <0.05).


Figure 1
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  		Fig. 1. (A) Renal tissue section of a rat in the control group shows normal microscopic findings (H&E, x400); (B) renal tissue section of a rat in the ischemia/reperfusion (IR) group shows a greater than 2/3 tubular profile of nuclear loss (H&E, x400); (C) renal tissue section of a rat in the zofenopril+IR group shows 1/3 tubular profile of nuclear loss (H&E, x400); (D) renal tissue section of a rat in the zofenopril-alone group shows normal microscopic findings, similar to the control groups (H&E, x400).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study shows that zofenopril prevented renal IR injury in rats. The data demonstrate that IR injury is related to oxidative processes and occurs in renal cells with activation of XO and development of inflammation. Zofenopril had protective effects against IR injury by reducing the production of free radicals, by scavenging free radicals, and by preventing inflammation. After renal IR injury, lipid peroxidation and protein oxidation were enhanced. Additionally, decreases of renal anti-oxidant enzyme activities, SOD and CAT, were observed in the IR group. There were 2 major findings, high MPO activity and high NO level, that may implicate increased inflammatory processes. The high MPO activity reflects neutrophil activation and the high NO level reflects iNOS activation.

We found higher renal NO levels and increased MPO activity in the IR rats compared to control rats. During the process of IR injury, inflammatory reactions are activated, resulting in the formation of inflammatory cytokines, such as tumor necrosis factor-{alpha}, interleukin-1, and arachidonic acid metabolites [24]. There is a strong relationship between cyclooxygenase-2 (COX-2) activity and renal IR injury. COX-2 is induced by cytokines to produce prostaglandins. Matsuyama et al [24] showed that COX-2 is expressed in rat kidney after IR injury. The most intense COX-2 expression occurred 3 to 5 hr after IR injury, whereas greatest tissue damage was seen 12 to 24 hr after IR injury.

In the present study, light microscopy showed that IR caused renal injury with tubular damage. Zofenopril treatment attenuated the effects of IR injury and prevented renal damage at biochemical and microscopic levels. Zofenopril treatment decreased lipid peroxidation as well as protein oxidation. The increased renal MPO activity and elevated NO level were lowered by zofenopril treatment in rats. During IR injury, a major source of free radicals is XO activation, as seen in our study. Zofenopril ameliorated the effect of IR to increase renal XO activity.

Reduced expression of oxidation-sensitive nuclear factor kappa B-dependent pro-inflammatory factors by ACE inhibitors has been reported in atherosclerotic rabbits [25]. In the present study, the protective effect of zofenopril treatment on the IR-induced renal NO level may be related to a reduction of nuclear factor kappa B-dependent pro-inflammatory factors, which play a major role in the activation of iNOS during the inflammatory process. A limitation of the present study that is NO production was measured by an indirect method. Some authors believe that such measurements provide little information concerning diffusible active NO [26]. They found that the indirect measurement of NO during endotoxemia failed to provide an accurate assessment of bioactive NO. Nevertheless, the measurement of nitrates and nitrites may serve as a rough estimate of the NO production in the tissue.

Sacco et al [13] demonstrated that an oral dose of zofenopril (15 mg/kg/day) prevented doxorubicin-induced cardiac injury in rats [13]. It is well known that doxorubicin causes cardiac injury by way of oxidative stress [8]. ACE activity in the heart, kidney, and serum was markedly reduced 4 hr after administration of zofenopril (10 mg/kg) and only partially returned toward control levels at 24 hr [12]. For these reasons, we used a daily oral dose of zofenopril (15 mg/kg/day) for 2 days, and we administered the first dose 1 day prior to the IR procedure. In general, zofenopril has good tolerability and is rapidly converted from prodrug to the active metabolite (zofenoprilat) [27]. Zofenopril is a sulfur-containing prodrug, which, after bio-conversion to its active free-sulfhydryl containing form, has 5-fold more potent anti-hypertensive effect than the ACE-inhibitor, captopril [15,28].

The finding that long-term treatment with the sulfhydryl ACE inhibitor, zofenopril, but not with a nonsulfhydryl ACE inhibitor, enalapril, improved the oxidative balance documents its sustained antioxidant activity in hypertensive patients [29]. Sulfhydryl compounds are a major class of protective agents against the free radicals generated by irradiation, neutralizing free radicals either by a hydrogen atom–donating reaction or an electron-transferring reaction [15]. ACE inhibition reduces angiotensin II–mediated macrophage lipid peroxidation [30]. Studies have shown that zofenopril has higher sulfhydryl-mediated free-radical scavenging activity and greater lipophilicity than captopril [31–33]. Rodriguez-Reynoso et al [34] reported that exogenous melatonin preserved renal function, increased glutathione levels, reduced lipid peroxidation, and prevented the rise in nitrite levels induced by renal IR without any significant effect on neutrophil infiltration. In contrast, in our study zofenopril prevented renal IR injury not only by antioxidant effects but also by anti-inflammatory effects, especially on MPO activity.

The mechanism of oxygen free radical repair mediated by sulfhydryl compounds may involve carbon-centered radicals. It appears that the protective effects of sulfhydryl agents correlate better with their direct hydroxyl radical scavenging abilities than with their antiperoxidative potency [15]. The non-sulfhydryl ACE inhibitor, enalapril, did not exhibit any vascular protection or antioxidant effects [11]. ACE is a widely distributed enzyme and its tissue concentration change in various pathologic conditions. Heart ACE activity increases in cardiac hypertrophy and after myocardial infarction [35] and treatment with ACE inhibitors is helpful for these myocardial diseases. It may be noted that renal endothelial and proximal tubular cells likewise produce more ACE in various kidney diseases [35].

In conclusion, the results of the present study suggest that zofenopril may prevent the renal IR injury that occurs during various conditions such as renal transplantation. Further studies are needed to delineate the exact mechanisms whereby zofenopril protects against renal oxidative damage.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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