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3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury Emin Oztas a; Ahmet Guven b; Erdal Turk b; Bulent Uysal c; Emin Ozgur Akgul d; Tuncer Cayci d; Nail Ersoz e; Ahmet Korkmaz c a Department of Medical Histology and Embrology, Gulhane Military Medical Academy, Etlik, Ankara, Turkey b Department of Pediatric Surgery, Gulhane Military Medical Academy, Etlik, Ankara, Turkey c Department of Physiology, Gulhane Military Medical Academy, Etlik, Ankara, Turkey d Department of Biochemistry, Gulhane Military Medical Academy, Etlik, Ankara, Turkey e Department of Surgery, Gulhane Military Medical Academy, Etlik, Ankara, Turkey Online Publication Date: 01 June 2009
To cite this Article Oztas, Emin, Guven, Ahmet, Turk, Erdal, Uysal, Bulent, Akgul, Emin Ozgur, Cayci, Tuncer, Ersoz, Nail and
Korkmaz, Ahmet(2009)'3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury',Renal Failure,31:5,393 — 399 To link to this Article: DOI: 10.1080/08860220902882741 URL: http://dx.doi.org/10.1080/08860220902882741
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Renal Failure, 31:393–399, 2009 Copyright © Informa Healthcare USA, Inc. ISSN: 0886-022X print / 1525-6049 online DOI: 10.1080/08860220902882741
LABORATORY STUDY LRNF
3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury Emin Oztas
Effects of 3-Aminobenzamide on Renal I/R
Gulhane Military Medical Academy, Department of Medical Histology and Embrology, Etlik, Ankara, Turkey
Ahmet Guven and Erdal Turk Gulhane Military Medical Academy, Department of Pediatric Surgery, Etlik, Ankara, Turkey
Bulent Uysal
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Gulhane Military Medical Academy, Department of Physiology, Etlik, Ankara, Turkey
Emin Ozgur Akgul and Tuncer Cayci Gulhane Military Medical Academy, Department of Biochemistry, Etlik, Ankara, Turkey
Nail Ersoz Gulhane Military Medical Academy, Department of Surgery, Etlik, Ankara, Turkey
Ahmet Korkmaz Gulhane Military Medical Academy, Department of Physiology, Etlik, Ankara, Turkey
Introduction. This study was designed to investigate whether 3-amino benzamide (3-AB), a poly (ADP-ribose) polymerase (PARP) inhibitor, has a protective effect on kidney injury induced by renal ischemia/reperfusion (I/R) by decreasing oxidative and nitrosative stress on renal dysfunction and injury. Materials and Methods. Thirty-two male SpragueDawley rats were divided into four groups: sham-operated, sham-operated + 3-AB, I/R, I/R + 3-AB. Rats were given 3-AB (100 mg/kg/day ip) 14 days prior to I/R. I/R and I/R + 3-AB groups underwent 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood were obtained for evaluation. Superoxide dismutase, glutathione peroxidase, malondialdehide, protein carbonyl content, and nitrite/nitrate level (NOx) were determined in the renal tissue. Serum creatinine (SCr), blood urea nitrogen (BUN), and aspartate aminotransferase (AST) were determined in the blood. Additionally, renal sections were used for histological grade of renal injury. Results. 3-AB
Received 3 February 2009; accepted 25 February 2009. Address correspondence to Ahmet Guven, MD, Gulhane Military Medical Academy, Department of Pediatric Surgery, 06018 Etlik, Ankara, Turkey; Tel.: +90 312 3045483; Fax: +90312-3042150; E-mail:
[email protected]
significantly reduced the I/R-induced increases in SCr, BUN, and AST. In addition, 3-AB markedly reduced elevated oxidative stress product, restored decreased antioxidant enzymes, and attenuated histological alterations. Moreover, 3-AB attenuated the tissue NOx levels, indicating reduced NO production. Conclusions. 3-AB has beneficial effect on renal glomerular and tubular dysfunction in rats’ kidneys subjected to I/R injury. Moreover, 3-AB has ameliorating effect on both oxidative stress and nitrosative stress of the kidneys, which correlated with histopathological evaluation. Keywords 3-aminobenzamide, renal ischemia/reperfusion, oxidative stress, poly (ADP-ribose) polymerase
INTRODUCTION Cessation of kidney blood supply leads to acute renal failure (ARF), causing failure of the kidneys over a period of hours or days. ARF is potentially reversible with appropriate management; otherwise, chronic renal failure (CRF) develops and causes the irreversible destruction of kidney tissue by progressive renal disease leading to end-stage renal failure. Despite significant advances in critical care
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medicine, ARF remains a major clinical problem associated with considerable morbidity and mortality.[1,2] The causes of ARF are multifactorial, but ischemic ARF caused by hypotension followed by resuscitation is common, the etiology of which is reflected in animal models of renal ischemia/reperfusion (I/R).[1,3] Despite our current knowledge of the pathophysiology underlying the development of ARF, the cellular mechanisms involved are complex and still not be fully understood. Pharmacological interventions that have targeted specific mechanisms have shown promise in laboratory-based experimental models but have not reduced the mortality associated with ARF in clinical studies. Thus, dialysis and transplantation remain the current viable therapeutic interventions for clinical ARF.[2] Reperfusion following a period of ischemia of kidney causes the activation and adhesion of polymorphonuclear neutrophils (PMNL), with the release of proinflammatory substances and the formation of free radicals.[1,3,4] Moreover, nitric oxide (NO) derived by inducible NO synthase (iNOS) has beneficial roles as a messenger and host defense system. On the other hand, excessive NO production reacts with superoxide ions released from inflammatory cells, producing the potent oxidant peroxynitrite (ONOO−) and protein tyrosine nitration.[5,6] It has been shown that NO and ONOO− contribute to the evolution of several renal diseases, including immune-mediated glomerulonephritis, obstructive nephropathy, renal I/R injury, and acute and chronic renal allograft rejection.[7] In our previous studies, we have shown that the inhibition of iNOS and scavenging of ONOO− reduced the damage in the kidneys subjected to renal I/R.[5,6] Studies have shown that ONOO® induces cellular injury by activation of poly (ADP-ribose) polymerase (PARP) through damaging DNA. Deoxyribonucleic acid damage is repaired via the activity of several DNA repair enzymes, including PARP enzymes. Extensive DNA damage may lead to excessive PARP activation, which consumes large quantities of cellular nicotinamide adenine dinucleotide (NAD+), resulting in adenosine triphosphate (ATP) depletion and cellular death. It has been postulated that inhibition of activity of PARP may prevent cell death.[8–11] Therefore, this study was designed to investigate whether 3-amino benzamide (3-AB), a PARP inhibitor, has a protective effect on kidney injury induced by renal I/R by decreasing oxidative and nitrosative stress.
MATERIALS AND METHODS Animals and Surgery The project was approved by the Experimental Ethics Committee of Gulhane Military Medical Academy,
Ankara, Turkey, and the National Institute of Health’s Guide for the Care and Use of Laboratory Animals was followed. Thirty-two male Sprague-Dawley rats, weighing 250–300 g, were provided by the Gulhane Military Medical Academy, Experimental Research Council, and housed in standard cages at a constant temperature (24°C), humidity (30%), and light-dark cycle in a controlled environment. Rats were under standard rat chow and water ad libitum. Rats were randomly divided into four groups: shamoperated (n = 8), sham-operated+3-AB (n = 8), renal I/R (n = 8), and renal I/R + 3-AB (n = 8). Sham-operated + 3-AB and renal I/R + 3-AB groups received 3-AB (10 mg/kg) intraperitoneally 6 h prior to ischemia and at the beginning of reperfusion. Following a 12 h fasting period, animals were anesthetized with an intraperitoneal injection of ketamine hydrochloride (50 mg/kg) and xylazine (10 mg/kg). The rats were placed on a heating pad kept at 39°C to maintain constant body temperature. A midline incision was made, the renal pedicle observed and arteries bilaterally occluded with an atraumatic microvascular clamp (Bulldog Artery Clamp, Harvard Apparatus, Holliston, Massachusetts, USA) for 60 min. The time of ischemia was chosen to maximize reproducibility of renal functional impairment while minimizing mortality in these animals. After 60 min of renal ischemia, clamps were removed and the kidneys were inspected for restoration of blood flow. The abdomen was closed in two layers. Sham-operated animals underwent the same surgical procedure without clamp application. Following a period of 6 h of reperfusion, animals were killed by cervical dislocation. At the time of death, blood was collected by heart puncture for measurement of biochemical analysis. Both kidneys were harvested for histopathological evaluation and biochemical examination.
Biochemical Analysis Serum samples were used for the measurement of blood urea nitrogen (BUN) and serum creatinine (SCr) levels, which were used as indicators of impaired glomerular function, and aspartate aminotransferase (AST), which was used as an indicator of renal I/R injury.[12] BUN, SCr, and AST were determined with an Abbott-Aeroset autoanalyzer (Chicago, Illinois, USA) using original kits. The frozen tissues were homogenized in phosphate buffer (pH 7.4) by means of a homogenizator (Heidolph Diax 900; Heidolph Elektro GmbH, Kelhaim, Germany) in an ice cube. The supernatant was allocated into 2 or 3 in separate tubes and stored at −70°C again. First of all, the protein content of tissue homogenates was measured by the method of Lowry et al. with bovine serum albumin as
Effects of 3-Aminobenzamide on Renal I/R
the standard. The efficacy of treatment was assessed by tissue level of malondialdehyde (MDA) using the method of Ohkawa et al., protein carbonyl content (PCC) using the method of Levine et al., superoxide dismutase (SOD) using the method of Sun et al., and glutathione peroxidase (GPx) using the method of Paglia and Valentine. Nitrate plus nitrite (NOx) levels, end products of nitric oxide degradation, were measured using the method described by Miranda et al., as we described in our previous works.[5,6]
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Histopathologic Evaluation Both kidneys of each animal were taken for histopathologic evaluation. In all groups, samples of kidney were placed in formalin and processed through to paraffin. They were subsequently sectioned at 5 μm and stained with Hematoxiline-Eosine (H&E). The sections were scored with a previously described semiquantitative scale designed to evaluate the degree of renal damage (tubular cell necrosis, cytoplasmic vacuole formation, hemorrhage and tubular dilatation).[13] A minimum of 10 fields for each kidney slide was examined and assigned for severity of changes. The scoring system used was 0, absent; 1, present; and 2, marked. Total histopathologic injury score per kidney was calculated by addition of all scores. Blind analysis of the histological samples was performed by two independent experts.
Statistical Analysis All data are expressed as mean ± standard error of the mean (SEM). All statistical analyses were carried out using SPSS statistical software (SPSS for Windows, Version 15.0, Chicago, Illinois, USA). Differences in measured parameters among the three groups were analyzed by Kruskal-Wallis test. Dual comparisons between groups that present significant values were evaluated with Mann-Whitney U test. Statistical significance was accepted a value of p < 0.05.
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RESULTS There were no significant differences between shamoperated and sham-operated + 3-AB group in terms of biochemical and histopathologic analysis (p > 0.05 shamoperated vs. sham-operated + 3-AB).
Renal Function Markers There was a significant increase in the SCr and BUN levels in the I/R group with compared to sham-operated groups, suggesting a significant degree of glomerular dysfunction (p < 0.01) (see Table 1). The administration of 3-AB significantly decreased the SCr and BUN levels in the I/R + 3-AB group (p < 0.05, I/R vs. I/R + 3-AB). Renal I/R produced a significant increase in the serum AST level, used as a marker of renal injury; however, serum concentration of AST was significantly decreased in the I/R + 3-AB (p < 0.01, I/R + 3-AB vs. I/R group; see Table 1).
Antioxidant Enzyme Activities Antioxidant enzyme activities (SOD and GSH-Px) were significantly the lowest in the I/R group (p < 0.01, I/R group vs. the other groups). On the other hand, antioxidant enzyme activities were significantly increased in the I/R + 3-AB group (p < 0.05, I/R vs. I/R + 3-AB group; see Table 2).
Oxidative and Nitrosative Stress Markers The rats subjected to renal I/R revealed a strike increase in the tissue MDA and PCC levels, suggesting increased lipid peroxidation and protein oxidation. The administration of 3-AB revealed a significant decrease
Table 1 Biochemical evaluation of serum for each group
Sham (n = 8) Sham + 3-AB (n = 8) I/R (n = 8) I/R + 3-AB (n = 8)
Creatinine (mg/dL)
BUN (mg/dL)
AST (IU/L)
0.51 ± 0.15 0.45 ± 0.32 1.87 ± 0.86*† 0.95 ± 0.85*‡
23.85 ± 3.12 26.63 ± 5.32 67.43 ± 8.28*† 43.16 ± 7.46*‡
122 ± 24 167 ± 42 426 ± 53*† 325 ± 38*‡
*Significantly different from Sham and Sham + 3-AB groups. † Significantly different from I/R+3-AB group. ‡ Significantly different from I/R group.
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E. Oztas et al. Table 2 Biochemical evaluation of kidney for each groups
Sham (n = 8) Sham + 3-AB (n = 8) I/R (n = 8) I/R + 3-AB (n = 8)
MDA (nmol/g-protein)
PCC (nmol/g-protein)
NOx (μmol/g-tissue)
SOD (U/g-protein)
GSH-Px (U/g-protein)
0.41 ± 0.2 0.44 ± 0.2 1.32 ± 0.6*† 0.63 ± 0.3*‡
0.69 ± 0.3 0.74 ± 0.4 1.6 ± 0.4*† 0.91 ± 0.5*‡
32.4 ± 5.2 38.7 ± 6.7 62.5 ± 6.5*† 47.4 ± 5.7*‡
519.9 ± 175.4 542.2 ± 132.5 291.2 ± 101.8*† 453.9 ± 119.8‡
4.14 ± 1.57 4.05 ± 0.84 4.71 ± 1.51*† 4.54 ± 0.82‡
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*Significantly different from Sham and Sham + 3-AB groups. † Significantly different from I/R + 3-AB group. ‡ Significantly different from I/R group.
in the levels of MDA and PCC in the rats subjected to renal I/R (p < 0.01, I/R vs. I/R + 3-AB group; see Table 2). NOx level (nitrite/nitrate concentration) in the renal tissue, as used indicator of NO production, was significantly increased in the rats subjected to renal I/R (p < 0.01, I/R vs. the other groups). Increased tissue NOx levels were significantly decreased in the I/R + 3-AB (p < 0.05, IR + 3-AB vs. I/R; see Table 2).
Histopathologic Evaluation Histopathologic grading of renal injury is displayed as median (min-max) (see Table 3). There were no significant differences between sham-operated and sham-operated + 3-AB groups, so we combined these groups into one group as control group. The total injury score was significantly increased in the I/R group indicating significant renal injury (p < 0.01, I/R vs. the other groups). On the other hand, total histological injury score was significantly decreased in the I/R + 3-AB group (p < 0.05, I/R + 3-AB vs. I/R). Representative histological samples from all groups are displayed in Figure 1.
Table 3 Histopathologic evaluation of kidney sections for each group Histopathologic scores of renal injury Sham (n = 8) Sham + 3-AB (n = 8) I/R (n = 8) I/R + 3-AB (n = 8)
0 (0–0) 0 (0–0) 3 (2–4)*† 1 (1–3)*‡
*Significantly different from Sham and Sham + 3-AB groups. † Significantly different from I/R + 3-AB group. ‡ Significantly different from I/R group.
DISCUSSION To find out new therapeutic modalities in ARF, we have investigated effects of 3-AB in a rat model of renal I/R injury. Our finding clearly revealed that 3-AB has a beneficial effect on renal glomerular and tubular dysfunction in rats’ kidneys subjected to I/R injury. Moreover, 3-AB has an ameliorating effect on both oxidative stress and nitrosative stress of the kidneys, which correlated with histopathological evaluation. Although oxidative stress holds the initial step in the pathogenesis of I/R injury, overexpression of iNOS changes the nature from oxidative to nitrosative stress. Once ONOO− forms, it induces both apoptosis and necrosis of cells.[14–16] In this mechanism, activation of the DNA repair enzyme PARP-1, a member of PARP enzyme family, mediates ONOO−-induced necrosis. PARP-1 detects and signals DNA strand breaks induced by a variety of genotoxic insults, including ionizing radiation, alkylating agents, oxidants (essentially OH•, ONOO−), and free radicals.[17–21] Upon binding to DNA, strand breaks occur, and PARP transfers ADP-ribose units from the respiratory coenzyme NAD+ to various nuclear proteins. From a physiological viewpoint, PARP-1 activity and poly (ADP-ribosyl)ation reactions are implicated in DNA repair processes, the maintenance of genomic stability, the regulation of gene transcription, and DNA replication. An important function of PARP-1 is to allow DNA repair and cell recovery under conditions associated with a low level of DNA damage. In case of severe DNA injury, overactivation of PARP-1 depletes the cellular stores of NAD+, an essential cofactor in principal energy production mechanisms, including the glycolytic pathway, the tricarboxylic acid cycle, and the mitochondrial electron transport chain. As a result, the loss of NAD+ leads to a marked reduction in the cellular pools of ATP, resulting in cellular dysfunction and death via the necrotic pathway.[14,15] This is known as the “suicide hypothesis” of PARP activation and seems to be a regulatory mechanism
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Figure 1. Representative histological photograph of cortical and medullar renal tissues. Upper row: Sham-operated animals: normal kidney tissue, normal histological characteristic of glomeruli and tubules. Middle row: Rats subjected to renal I/R injury marked tubular cell necrosis, cytoplasmic vacuole formation, hemorrhage, and tubular dilatation. The major changes in tubules including hemorrhage in medulla of kidney are remarkable. Lower row: Rats subjected to renal I/R injury, pretreated with 3AB moderate kidney damage, focal tubular necrosis, and moderate dilatation of the tubular structure and moderate medullar hemorrhage. In comparison with the I/R, the 3AB-treated group shows preservation of the kidney tissue. (H&E, Scale bars: 50 micron)
to eliminate cells after irreversible DNA injury. A vast amount of experimental evidence has established that the PARP-1 pathway of cell death plays a pivotal role in tissue injury and organ dysfunction in numerous disease processes.[8,18,22,23] The inhibition of PARP using 3-AB significantly improved renal functions, as evidenced by reduction in the levels of SCr, BUN, and AST as compared to vehicletreated and sham-operated animals. Histological evaluation of ischemic kidneys derived from animals that were treated with PARP inhibitor demonstrated improved histology, as shown by a decreased number of dilated tubules,
restored epithelial structures, and inhibited recruitment of neutrophils. The restoration of normal renal functions following an ischemic insult depends to a great extent on the regeneration of the damaged epithelial cells. A major requirement for initiation of the cell survival and regeneration process is the repletion of cellular ATP levels. Therefore, the enhanced restoration of the injured kidney in the setting of PARP inhibition may partly be due to the protection of the epithelial cells as evidence of decreased the suicide hypothesis of PARP activation. We evaluated the tissue injury markers (MDA and PCC) and the tissue antioxidant system (SOD and GSH-Px). Data
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revealed that the inhibition of PARP significantly ameliorated oxidative and nitrosative stress—in other words, PARP activation contributed to I/R injury in the kidney. PARP activation can contribute to I/R injury via multiple mechanisms. PARP activation is likely to up-regulate activities of both extramitochondrial NADPH oxidase and mitochondrial NADH oxidase, the important superoxidegenerating enzymes.[24] On the other hand, PARP activation alters transcriptional regulation and activates nuclear factorkB, activator protein-1, signal transducer and activator of transcription-1, among others.[9] Such activation leads to increased formation of endothelin-1and inflammatory cytokines (i.e., tumor necrosis factor-a, interleukin-6, and interleukin-1b1, all known to contribute to superoxide generation).[9,11] Therefore, PARP activation may contribute to renal cellular dysfunction by triggering alternative mechanism. Further studies are clearly needed to clarify the exact mechanism of oxidative stress and PARP activation. The earlier investigations related to the role of PARP activation with renal injury yielded controversial results. Later studies, however, clearly demonstrated that PARP activation contributes to the pathogenesis of ARF in ischemic kidneys.[9,11] Similar to these results, current study demonstrated that 3-AB ameliorates on both oxidative and nitrosative stress in ARF induced by renal I/R injury. Furthermore, results from our laboratory and others clearly suggest that pharmacological manipulation of PARP activity may produce salutary effects in the setting of ARF.[9,10,25] Possible explanations for this observation come from the studies suggesting the role of PARP in leukocyte-dependent inflammation. These studies have shown that PARP inhibition can completely abrogate the release of cytokines and also led to the attenuated the recruitment of neutrophils.[9,26] It was also shown that PARP inhibition attenuates nitrite/nitrate production in a model of systemic endotoxemia,[25,27] as also seen in the current study. Thus, we speculate that ameliorated oxidative and nitrosative stress in rats received 3-AB might be attributed to its regulation of transcription and inflammatory response. In conclusion, pharmacological inhibition of PARP activity in the setting of ARF offered protection against the renal I/R injury. However, whatever the basis for beneficial action of 3-AB may be, our findings provide a rationale for using of inhibitors of PARP to ameliorate ARF. Further studies should be assessed to determine the side effect of this agent.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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