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CARDIOVASCULAR ANESTHESIA

Isoflurane Protects Renal Function Against Ischemia and Reperfusion Through Inhibition of Protein Kinases, JNK and ERK

Department of Anesthesiology, Department of Histology, Nagasaki University School of Medicine, Nagasaki, Japan

Address correspondence and reprint requests to Koji Sumikawa, MD, Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1, Sakamoto, Nagasaki 852–8501, Japan. Address e-mail to cds93710{at}syd.odn.ne.jp.

	Abstract

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Isoflurane has a pharmacological preconditioning effect against ischemia in the heart and brain, but whether this also occurs in the kidney is unclear. In this study, we investigated pharmacological preconditioning by isoflurane in the rat kidney. In the isoflurane preconditioning group (1.5% isoflurane for 20 min before renal ischemia) serum creatinine (1.2 ± 0.7 and 1.1 ± 0.2 mg/dL) and blood urea nitrogen (99 ± 29 and 187 ± 31 mg/dL) were significantly smaller at 24 and 48 h after reperfusion than in the nonpreconditioning group (creatinine; 2.4 ± 1.2 and 2.9 ± 0.9 mg/dL, urea; 62 ± 19 and 79 ± 20 mg/dL). We also investigated the intracellular signal transduction involved in isoflurane preconditioning in the kidney. The activities of the stress protein kinases, JNK and ERK but not p38, were significantly less in the kidneys of the preconditioning group than in those of the nonpreconditioning group (P < 0.05). We conclude that isoflurane has a preconditioning effect against renal ischemia/reperfusion injury when administered before ischemia. Inhibition of the protein kinases, JNK and ERK, might be involved in the mechanisms of isoflurane preconditioning.

	Introduction

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Renal ischemia/reperfusion injury is associated with frequent morbidity and mortality (1). Improving the ability of the kidney to tolerate ischemia/reperfusion injury would have important implications. Although the introduction of better preservative solutions has reduced the severity of ischemic lesions, ischemia/reperfusion injury remains a major problem in renal transplantation and anesthesia.

A number of drugs appear to mimic ischemic preconditioning. This phenomenon, called "pharmacological preconditioning," has been demonstrated with nicorandil, opioid receptor agonists, and volatile anesthetics (2–4). Volatile anesthetics, including isoflurane, have a pharmacological preconditioning effect in the heart (3) and brain (4). There is evidence that renal ischemic preconditioning exists (5). However, the effect of isoflurane on renal ischemia/reperfusion injury is not clear. A variety of mechanisms have been discussed to explain the beneficial role of pharmacological preconditioning; however, the exact underlying mechanisms of protection are still unknown. Ischemia/reperfusion injury is a complex process involving the generation and release of inflammatory cytokines, the accumulation and infiltration of neutrophils, and cell death (6). Several studies have reported that both ischemic and pharmacological preconditioning attenuated inflammation (7–10) and cell death (11,12).

Mitogen-activated protein kinases (MAPKs), such as JNK, p38, and ERK, phosphorylate-specific serines and threonines of target protein substrates and affect gene expression, mitosis, cytokinesis, and cell survival, necrosis, and apoptosis (13). MAPKs mediate the response of cells to a wide variety of physiological and stress-related stimuli, including ultraviolet light, ischemia/reperfusion and hyperosmolality. Several studies suggest that members of the MAPK family are activated in the kidney after ischemia and reperfusion (14–16). It has been proposed that the relative extent of JNK, p38, and ERK activation determines cell fate after ischemia/reperfusion injury. These kinase signaling pathways may, therefore, be an important molecular component responsible for tissue injury after ischemia/reperfusion in the kidney.

In this study, we investigated whether isoflurane protects against ischemia/reperfusion injury in the rat kidney and whether it does so by influencing the activity of the MAPK family of stress protein kinases.

	Methods

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After approval of Animal Care Committee, male Wistar rats weighing 220–300 g were anesthetized with pentobarbital sodium (60 mg/kg intraperitoneally). The trachea was intubated, and the lungs were mechanically ventilated with air (Natsume Seisakusho CO, Tokyo, Japan).

In some animals, a catheter was placed in the femoral artery for continuous monitoring of arterial blood pressure. A rectal probe (Sibauradensi CO, Tokyo, Japan) was inserted to monitor body temperature, which was maintained at 36°C–37°C by a heating lamp (Sanae CO, Tokyo, Japan). Before surgery, rats received local infiltration anesthesia in the surgical field and the kidneys were exposed through flank incisions. Two separate studies were performed for measuring renal function and activities of protein kinases.

Animals were randomly divided into three groups. Rats in the sham group (n = 8) underwent sham surgery only. Groups ischemia/no-isoflurane (n = 8) and ischemia/isoflurane (n = 8) were subjected to bilateral renal ischemia for 40 min by clamping both renal pedicles with atraumatic microaneurysm clamps. Renal ischemia was judged by the color change, and renal blood flow was measured by Doppler before and after clamping (Doppler-1010-A; Parks Co, OR). Rats in the ischemia/isoflurane group received 1.5% isoflurane for 20 min before renal ischemia. The flank incision was closed in two layers and covered with antibiotic ointment. Blood samples were obtained from the tail vein at 0, 12, 24, and 48 h after reperfusion, and serum creatinine and blood urea nitrogen were determined using the Jaffe reaction (17) and urease/GLDH test (18).

Animals were randomly divided into four groups. Groups ischemia/no-isoflurane and ischemia/isoflurane were subjected to 40-min left renal ischemia by clamping the renal pedicles with atraumatic microaneurysm clamps. The right kidney was used as a control in each animal. Rats in the sham group received 1.5% isoflurane before sham surgery. Renal ischemia and reperfusion were judged by the renal complexion and renal blood flow was measured by Doppler before and after clamping. Rats in the ischemia/isoflurane group received 1.5% isoflurane for 20 min before renal ischemia. Ischemic kidneys were harvested at 0, 5, 40, and 90 min (all n = 4) after starting reperfusion in both groups and each sham kidney was harvested at 40 min (all n = 4) after sham surgery, for measurement of JNK, p38, and ERK activities. The activities were assessed using gel electrophoresis and Western blotting. For quantitative analysis of the densities of the immunoblot bands (JNK, p38, and ERK), the densities were quantitated using the densitometric scanning image analysis system (NIH Image analyzer 1.60; National Institutes of Health, Bethesda, MD). Four kidneys were analyzed to obtain the mean value for one observation point.

For gel electrophoresis and Western blotting of active forms of JNK, p38, and ERK, the kidneys were homogenized and diluted with sample buffer (20 mM Tris-HCl(pH 7.4), 1 mM EDTA, 1 mM EGTA, 150 mM NaCl, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM sodium orthovanadate, 1 µg/mL leupeptin, and 1 mM phenylmethylsulfonyl fluoride). The protein content was determined using the method of Bradford (19). Equal amounts of protein were loaded in each lane. Protein analyzed on gel electrophoresis was transferred to nitrocellulose membranes (Invitrogen Japan; Tokyo, Japan) using an electrophoretic transfer system (Semi-Dry Transfer System; Biocraft, Tokyo, Japan) at 150 V, 200 mA for 85 min. After the membranes were transferred, they were washed with Tris-buffered saline (TBS: 25 mM Tris-HCL pH 7.6, 200 mM NaCl). The blots were blocked in TBS containing 5% nonfat dry milk for 60 min. The membranes were incubated overnight at 4°C, with the primary rabbit anti-phosphorylated polyclonal antibody against c-jun for JNK, ATF-2 for p38, and Elk-1 for ERK (New England BioLabs, Ipswitch, MA) diluted 1:1000 with primary antibody dilution buffer. After washing with Tris-buffered saline-Tween 20 (TBST), the membranes were incubated with secondary antibody (anti-rabbit immunoglobulin G-alkaline phosphatase conjugate; New England BioLabs) diluted 1:2000 for 1 h at room temperature and again washed with TBST. The membranes were incubated with LumiGLO and peroxide (New England BioLabs), agitated for 1 min at room temperature, and exposed to Kodak radiograph film. The immunoreactive bands were visualized using the enhanced chemiluminescence method, and the densities were measured by NIH Image analyzer.

For histological examination, tissue samples from the kidneys in groups sham (underwent sham surgery only) (n = 4), ischemia/no-isoflurane (n = 4), and ischemia/isoflurane (n = 4) were removed at 48 h after surgery. They were bisected along the long axis, cut into 3 equal-sized slices, and fixed with 10% formalin overnight. After dehydration and embedding in paraffin, 4-µm sections were stained with hematoxylin and eosin. Morphological assessment was performed by a pathologist who was unaware of the treatment that the animal had received. Renal injury (acute tubular necrosis) was graded on a scale of 0 to 4, as described by Jablonski et al. (20).

Data are reported as mean ± sd. Renal function data were analyzed with one-way analysis of variance. Scheffé's post hoc test was used for multiple comparisons. Western blot signals were analyzed by Student's t-test. Histopathologic examination was analyzed by the Kruskal-Wallis test. A value of P < 0.05 was considered statistically significant.

	Results

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The values of serum creatinine in the ischemia/no-isoflurane group were 2.4 ± 1.2 mg/dL and 2.9 ± 0.9 mg/dL at 24 and 48 h after reperfusion, and those in ischemia/isoflurane group were significantly lower, 1.2 ± 0.7 mg/dL and 1.1 ± 0.2 mg/dL at 24 and 48 h (Fig. 1). The values of blood urea nitrogen in the ischemia/no-isoflurane group were 99 ± 29 mg/dL and 187 ± 31 mg/dL at 24 and 48 h after reperfusion, and those in group ischemia/isoflurane were significantly lower, 62 ± 19 mg/dL and 79 ± 20 mg/dL at 24 and 48 h. In the sham group, there were no significant differences in serum creatinine and blood urea nitrogen at 12, 24, or 48 h. We measured arterial blood pressure in all groups. At the concentration used in this study, the effects of isoflurane on arterial blood pressure were minimal, as previously described (21).

View larger version (12K): [in this window] [in a new window]   Figure 1. Serum creatinine at 0, 12, 24, and 48 h (all n = 8) after surgery from sham-operated rats (sham), ischemia/no-isoflurane group (bilateral renal ischemia for 40 min), and ischemia/isoflurane (pretreated 1.5% isoflurane for 20 min before renal ischemia for 40 min) rats. Isoflurane blunted a significant increase of serum creatinine after renal ischemia/reperfusion. Data are expressed as mean ± sd. #P < 0.01 compared with sham; *P < 0.01 compared with group ischemia/no-isoflurane.

JNK, p38, and ERK were all markedly activated by 5 min after starting reperfusion. JNK activity peaked at 40 min and remained at a relatively high level until 90 min after starting reperfusion. p38 activity peaked at 90 min and ERK activity peaked at 5 min. ERK activity remained at a relatively high level until 90 min after starting reperfusion (Fig. 2).

View larger version (43K): [in this window] [in a new window]   Figure 2. In group ischemia/no-isoflurane (bilateral renal ischemia for 40 min), kidneys were harvested at 0, 5, 40, and 90 min (all n = 4) after starting reperfusion and each sham kidney was harvested at 40 min (all n = 4) after sham surgery, for measurement of JNK, p38, and ERK activities. JNK, p38, and ERK were activated as early as 5 min after reperfusion but remained at relatively high levels up to 90 min after reperfusion. Densities of Western blot bands were quantified by the NIH Image program. Densitometry of JNK, ERK and p38 bands are expressed in arbitrary units.

The activity of JNK in the ischemia/isoflurane group was significantly less than that in the ischemia/no-isoflurane group from 40 to 90 min after starting reperfusion (P < 0.05) (Fig. 3). The activity of ERK in the ischemia/isoflurane group was significantly less than that in the ischemia/no-isoflurane group from 5 to 90 min after starting reperfusion (P < 0.05) (Fig. 3). There was no significant difference in the activity of p38 between the ischemia/no-isoflurane and ischemia/isoflurane groups (Fig. 3).

View larger version (19K): [in this window] [in a new window]   Figure 3. In groups ischemia/no-isoflurane (bilateral renal ischemia for 40 min) and ischemia/isoflurane (pretreated 1.5% isoflurane for 20 min before renal ischemia for 40 min), kidneys were harvested at 0, 40, and 90 min (all n = 4) after starting reperfusion and each sham kidney was harvested at 40 min (all n = 4) after sham surgery for measurement of JNK, p38, and ERK activities. The activity of JNK and ERK in group ischemia/isoflurane was significantly less than that in group ischemia/no-isoflurane from 40 to 90 min after starting reperfusion (P < 0.05). The activity of p38 did not differ between the two groups. Densities of Western blot bands were quantified by the NIH Image program. Densitometry of JNK, ERK, and p38 bands are expressed in arbitrary units. Data are expressed as mean ± sd. *P < 0.05 compared with ischemia/no-isoflurane group.

Ischemia/reperfusion was associated with renal tubular necrosis, particularly in the distal proximal tubules of the outer medullary area, compared with sham-operated rats (Fig. 4). Administration of isoflurane significantly decreased the extent of tubular necrosis at 48 h after reperfusion (Fig. 4). Glomerular injury was marginally detected after ischemia/reperfusion injury in the ischemia/no-isoflurane and ischemia/isoflurane groups. Histological grading at 48 h after surgery significantly improved renal morphology in the preconditioning group (group ischemia/isoflurane) compared with the group without preconditioning (group ischemia/no-isoflurane) (Fig. 5).

View larger version (159K): [in this window] [in a new window]   Figure 4. Microscopic findings of kidneys after surgery at 48 h from sham-operated (sham surgery only), group ischemia/no-isoflurane (bilateral renal ischemia for 40 min), group ischemia/isoflurane (1.5% isoflurane for 20 min before renal ischemia for 40 min). Histopathologic examination was performed using hematoxylin and eosin x200. Significant tubular necrosis is present in the cortex and outer medulla (outer stripe) after renal ischemia/reperfusion injury in the ischemia/no-isoflurane group. Administration of 1.5% isoflurane for 20 min before ischemia significantly decreased the extent of tubular necrosis at 48 h after reperfusion.

View larger version (9K): [in this window] [in a new window]   Figure 5. Representative histological finding from one animal for each of the four groups showing renal injury (acute tubular necrosis) graded on a scale of 0 to 4 20). Histologic grading at 48 h after surgery in the ischemia/isoflurane group (1.5% isoflurane for 20 min before renal ischemia for 40 min) was significantly improved compared with the ischemia/no-isoflurane group (bilateral renal ischemia for 40 min). Data are expressed as mean ± sd. #P < 0.05 versus ischemia/no-isoflurane.

	Discussion

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The present study showed that serum creatinine and blood urea nitrogen increase significantly 12, 24, and 48 hours after 40-minute renal ischemia and that 20 minutes of pretreatment with 1.5% isoflurane prevents this increase. Moreover, histopathologic examination of the kidneys of rats subjected to ischemia/reperfusion revealed severe renal damage and exposure to isoflurane before ischemia significantly reduced the damage, i.e., 1.5% isoflurane appeared to have a preconditioning effect.

Some studies show that an inflammatory response and cell death induced by ischemia/reperfusion is largely responsible for functional organ failure and tissue damage. The acute inflammatory response initiated by ischemia/reperfusion is characterized by the induction of a proinflammatory cytokine cascade, expression of adhesion molecules, and cellular infiltration (6,7).

Ischemic preconditioning has been reported to prevent and/or reduce ischemia/reperfusion-dependent tissue injury (8,11). A variety of mechanisms have been discussed to explain the beneficial role of ischemic preconditioning; however, the exact underlying mechanisms of protection are still unknown. Kharbanda et al. (8) reported that ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia/reperfusion. Glanemann et al. (11) reported that apoptosis and inflammation were markedly influenced by ischemic preconditioning, as well as by methylprednisolone administration before hepatic ischemia.

Volatile anesthetics, including isoflurane, have a pharmacological preconditioning effect in the heart (3) and brain (4). Liu et al. (10) showed that isoflurane and sevoflurane administration before ischemia inhibited the rate of increase of tumor necrosis factor. One report showed that isoflurane and halothane significantly attenuated the inflammatory response and that isoflurane pretreatment inhibited cytokine-induced cell death in cultured rat smooth muscle cells and human endothelial cells (9).

Several studies suggested that members of the MAPK family of protein kinases, such as JNK, p38, and ERK, are activated in the heart and kidney after ischemia and reperfusion (14–16,22). We have now shown that these kinases are activated by ischemia/reperfusion in the rat kidney. The MAPKs phosphorylate-specific serines and threonines of target protein substrates and affect gene expression, mitosis, cytokinesis, and cell survival, necrosis, and apoptosis (13). JNK and p38 activation are important in the control of cell death and enhance the expression of adhesion molecules (22) and cytokine production (23). Ishii et al. (7) reported that inhibition of c-jun NH(2)-terminal kinase activity improved ischemia/reperfusion injury in rat lungs via an antiinflammatory and antiapoptotic effect. Inhibition of c-jun N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anesthetized rats (12). Consistent with our data with ERK, Lee et al. (24) reported that inhibition of JNK or ERK improves lung injury. ERK, however, also plays a protective role in myocardial ischemia/reperfusion injury (25). The molecular mechanisms by which ischemia and reperfusion lead to cell death and eventually to tissue damage are poorly understood. However, these kinases signaling pathways may be an important molecular component responsible for tissue injury after ischemia/reperfusion in the kidney.

A limitation of our study is that we tested only a single dose, administration time, and ischemia time. Therefore, whether the protective effects of isoflurane are an "on-off" mechanism or a "dose-dependent" one was not elucidated in this study. However, the dose we used (1.5%) is within the clinical range. Isoflurane might therefore be beneficial in patients at risk of renal ischemia/reperfusion.

In conclusion, this study demonstrates that isoflurane has a preconditioning effect against renal ischemia/reperfusion injury. Isoflurane blunts the activation of JNK and ERK, but not that of p38, when administered before ischemia. The relative extent of JNK, p38, and ERK activation has been proposed to determine cell fate after injury. Therefore, blunting of the protein kinases, JNK and ERK, may be involved in the mechanisms of isoflurane preconditioning.

	Footnotes

 
Supported, in part, by Grant-in-Aid B 14571448 for Scientific Research from the Ministry of Education, Science and Culture, Japan.

Accepted for publication May 25, 2005.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Hashiguchi, H. Articles by Sumikawa, K. Search for Related Content PubMed PubMed Citation Articles by Hashiguchi, H. Articles by Sumikawa, K. Related Collections Pharmacology

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999