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(Journal of Leukocyte Biology. 2001;70:192-198.)
© 2001 by Society for Leukocyte Biology

IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury

Melissa J. Burne*, Asmaa Elghandour*, Mahmud Haq{dagger}, Sabiha R. Saba{dagger}, James Norman{dagger}, Thomas Condon{ddagger}, Frank Bennett{ddagger} and Hamid Rabb*

* Nephrology Division, Hennepin County Medical Center, University of Minnesota, Minneapolis;
{dagger} Department of Surgery and Pathology, University of South Florida, Tampa; and
{ddagger} ISIS Pharmaceuticals, Carlsbad, California

Correspondence: Hamid Rabb, MD, Division of Nephrology, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN, 55415. E-mail: rabbx003{at}tc.umn.edu


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ABSTRACT
 
In vitro studies have suggested that targeting interleukin (IL)-1 and tumor necrosis factor (TNF) can be used to regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and potentially treat kidney inflammation. We therefore evaluated ICAM-1 and VCAM-1 regulation in knockout (KO) mice deficient in both IL-1 receptor 1 (R1) and TNF-R1 during renal ischemia reperfusion injury. ICAM-1 and VCAM-1 mRNA expression was measured with specific murine probes and Northern blotting (n =4/group). Protein expression was measured using immunohistochemistry. Serum creatinine (SCr), tubular histology, and neutrophil infiltration into postischemic kidneys were also quantified. ICAM-1 and VCAM-1 mRNA expression increased in both wild-type (WT) and KO mice at 2, 6, and 24 h. Protein expression of ICAM-1 and VCAM-1 was also increased at 24 h postischemia. SCr levels and tubular necrosis scores were comparable in WT and KO mice at 24 and 48 h. Neutrophil migration in KO mice was decreased at 24 h but comparable to WT at 48 h. These data demonstrate that IL-1 and TNF are not essential for postischemic increases in ICAM-1 and VCAM-1.

Key Words: kidney injury • adhesion molecule expression • cytokines


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INTRODUCTION
 
The pathophysiological mechanisms leading to renal ischemia reperfusion injury (IRI) with delayed allograft function are not fully understood. It has been suggested that the outer-medullary vascular congestion seen in ischemic acute renal failure [1 ] might result partly from intercellular adhesion molecule-1 (ICAM-1)-mediated adhesion of leukocytes to the endothelium. Obstruction of the venous vasa recta and/or leukocyte-mediated increase in endothelial permeability leads to erythrocyte aggregation and edema [1 , 2 ]. During reduced flow, neutrophils adhere to vascular endothelium and occlude capillaries. Flow restoration may, however, fail to dislodge the adherent cells. Reperfusion of the kidney also triggers a cascade of responses including changes in cytokine synthesis, cell adhesion, leukocyte migration, and leukocyte-mediated tissue damage. Chemotactic stimuli released by ischemic tissue may also lead to leukocyte infiltration [3 ].

ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) are expressed by leukocytes and endothelial cells. ICAM-1 is found in abundance on endothelial, epithelial, and mesangial cells and fibroblasts. It is up-regulated in vitro and in vivo by cytokines such as interferon (IFN)-{gamma}, tumor necrosis factor (TNF), and interleukin (IL)-1 [4 ]. Interruption of the ICAM-1 pathway has been seen to lead to profound protection in various organ models of IRI [5 6 7 8 ]. The presumed mechanism of protection has been the blockade of intravascular adhesion and emigration of neutrophils to postischemic tissue. However, ICAM-1 has also been shown to mediate other functions, such as signal transduction [9 ] and antigen presentation [10 ]. VCAM-1 is constitutively expressed by glomerular parietal epithelial cells and is also detected on a wide variety of cells after stimulation with cytokines [4 ]. VCAM-1 has been shown to be important in recruitment of mononuclear cells to inflamed tissue [11 ]. This finding is of significance in that increasing evidence suggests a role of mononuclear leukocytes in renal IRI [12 , 13 ]. A number of studies have shown a direct role of ICAM-1 in IRI. ICAM-1 antibodies or antibodies against the ICAM-1 receptor, CD11/CD18, have been found to protect against both the functional impairment and histological changes associated with ischemic acute renal failure in the rat [14 15 16 ]. Interruption of the ICAM-1 pathway protects against renal IRI presumably by blocking the migration of leukocytes to postischemic tissue, as well as by attenuating microvascular obstruction.

ICAM-1 expression can be up-regulated by many cytokines and agonists, including IL-1, TNF, and IFN-{gamma} [10 , 17 18 19 ]. IL-1 and TNF are increased in the circulatory system [20 ]. We have also recently found that expression of IL-1 and TNF is increased in a murine model of renal IRI [21 , 22 ]. Administration of IL-1 to rats results in increased neutrophil infiltration of the kidney [23 ]. A recent study has also shown that IL-1 and TNF can regulate expression of leukocyte-binding adhesion molecules in endothelial cells derived from human glomerulus [24 ].

Either IL-1 or TNF produced by the postischemic kidney could up-regulate renal ICAM-1 and VCAM-1 expression. Blocking either one individually may be ineffective in regulating ICAM-1 and VCAM-1 because the the other pathway is available to compensate. We hypothesized, therefore, that combined IL-1 and TNF blockade would be more likely to reduce ICAM-1 and VCAM-1 expression after IRI, as well as less postischemic renal injury. To test these hypotheses, we evaluated ICAM-1 and VCAM-1 expression in mice deficient in both IL-1-R1 and TNF-R1 after subjecting them to renal IRI.


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MATERIALS AND METHODS
 
Knockout mice
The knockout (KO) mice used in this study were IL-1R1- and TNF-R1-deficient. Wild-type mice were littermates of the KOs. KO mice lack the major IL-1 receptor as well as the TNF receptor p55. Tail samples were obtained from these mice and analyzed by PCR to confirm the absence of targeted transcripts.

RNA isolation and analysis
Excised tissue was snap frozen in liquid nitrogen and then pulverized using a Bessman tissue pulverizer. Total cellular RNA was isolated by cellular lysis in 4 M guanidinium isothiocyanate followed by a CsCl gradient [25 ]. Total RNA was separated on a 1% agarose gel containing 1.1% formaldehyde, then transferred to a nylon membrane, and UV cross-linked to the membrane using a Stratagene UV cross-linker 2400 (Stratagene, San Diego, CA). Blots were hybridized with 32P cDNA probes that were randomly primed (Prime-a-Gene; ProMega, Madison, WI) and then purified on NAP-5 columns (Pharmacia) for 1–2 h in QuikHyb solution (Stratagene). Blots were washed twice at 25°C in 2x saline sodium citrate (SSC) with 0.1% sodium dodecyl sulfate (SDS) for 10 min each and then washed one time in 0.1% SSC with 0.1% SDS at 60°C for 20 min. Hybridizing bands were visualized and quantitated using a Molecular Dynamics PhosphorImager (Molecular Dynamics, Sunnyvale, CA). The blots were stripped by pouring boiling 0.1% SSC + 0.1% SDS solution on the blots and incubating under gentle agitation for 5 min. Blots were reprobed with glyceraldehyde 3-phosphate dehydrogenase (G3PDH) (Clontech, Palo Alto, CA) to confirm equal RNA loading.

Renal ischemia reperfusion model
This model of warm ischemia has been previously described in depth [26 ]. Briefly, mice weighing 25–35 g were anesthetized with intraperitoneal pentobarbital (35–60 mg/kg). Bilateral flank incisions were made, and the kidneys were exposed. The renal pedicles were bluntly dissected, and a nontraumatic vascular clamp (Roboz microaneurysm clamp; Roboz Surgical Instruments, Washington, DC) was applied across the pedicles for 30 min. At 2, 6, 24, and 48 h after ischemia, mice were euthanized, blood was collected by cardiac puncture, and kidney tissue samples were obtained.

Pathological evaluation
Kidneys were cut coronally and embedded in paraffin. Four-µm sections were stained with hematoxylin and eosin and Leder stains, reviewed in a blinded fashion by a renal pathologist and nephrologist, and scored with a previously described semiquantitative scale designed to evaluate the degree of tubular necrosis, with higher scores representing more severe damage [3 , 14 , 16 ]. A value of 0 is designated normal tissue, 1 is minimal necrosis (<5% involvement), 2 is mild necrosis (5–25% involvement), 3 is moderate necrosis (25–75% involvement), and 4 is severe necrosis (>75% involvement). Polymorphonuclear (PMN) cell infiltration into the interstitium was also quantified in the outer medulla, which is recognized as the area of maximal PMN cell migration. This was performed in 10 randomly selected high-power fields of the corticomedullary junction, as previously described [14 , 16 ].

Immunohistochemistry
Sections (5 µm) were prepared on a cryostat and mounted on Fisher Superfrost Plus slides, fixed in ice-cold acetone for 1–2 min, and allowed to air dry. These sections were then blocked with 1:100 normal rabbit serum in phosphate-buffered saline (PBS) containing Vector avidin DH (Vector Laboratories Inc., Burlingame, CA). Primary antibodies were then added to the sections; KAT-1 (rat anti-mouse ICAM-1, Biosource International, Camarillo, CA) and 429 (MVCAM.A) (rat anti-mouse VCAM-1, PharMingen, San Diego, CA) and incubated at room temperature for 1 h. Background-staining isotype controls consisted of rat IgG1.K in place of the monoclonal antibody. Sections were then rinsed in PBS and treated with 3% hydrogen peroxide in Biotin (10 µg/L of PBS) to block the biotin-binding sites. After three washes in PBS, the slides were incubated in a biotin-conjugated rabbit anti-rat IgG secondary antibody (Vector Laboratories Inc, Burlingame, CA) for 35 min at room temperature. Sections were once again washed and incubated for 45 min in Vector Elite ABC (Vector Laboratories Inc, Burlingame, CA). Sections were washed and developed with 3,3-diaminobenzidine (Vector Laboratories Inc, Burlingame, CA), counterstained with hematoxylin, and mounted using permount (Fisher Scientific, Pittsburgh, PA). Tissue sections were examined for positive staining, and representative photos were taken.

Renal function
Renal function was assessed by measurement of serum using a 550 Express autoanalyzer (Ciba Corning, Oberlin, OH). Serum creatinine, a byproduct of muscle metabolism, is normally excreted by the kidneys. In the absence of changes in muscle breakdown, serum creatinine levels correlate well with glomerular filtration rate. The degree of renal dysfunction can therefore be assessed by a rise in serum creatinine after injury.

Statistical analysis
Data are presented as means ± SE. Statistical analysis comparing control and KO groups was performed by analysis of variance and Fisher’s least-significant-difference test. Significance was set at P < 0.05.


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RESULTS
 
Confirmation of KO status
PCR analysis of tail samples from wild-type and KO mice confirmed the dual-receptor KO status (Fig. 1 ).



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  		Figure 1. Confirmation of IL-1R and TNF-R KO status in the dual-knockout mouse by PCR analysis of tail samples.

Postischemia up-regulation of ICAM-1 and VCAM-1
Northern blots of renal mRNA from wild-type and KO mice are represented in Figure 2 . The KO mice showed up-regulation of both ICAM-1 mRNA and VCAM-1 mRNA at 2 and 6 h postischemia, with further up-regulation of ICAM-1 at 24 h. Wild-type mice also showed up-regulation of ICAM-1 and VCAM-1 expression 2 and 6 h postischemia. G3PDH-1 expression, which was used as a control for gel loading, was constant in both wild-type and KO mice postischemia.



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  		Figure 2. Northern blot analysis showing up-regulation of ICAM-1 and VCAM-1 at 2, 6, and 24 h postischemia in IL-1R1/TNF-R1 KO mice (DKO) and wild-type control mice (C57). The gene encoding G3PDH-1 was used as a housekeeping gene.

Figure 3 represents postischemic ICAM-1 mRNA levels in KO mice and wild-type control mice (n =4/group). Baseline values in normal kidneys were calculated and represent 100%. Wild-type and KO levels were determined and quantified according to baseline values of 100% and corrected for changes in loading with G3PDH-1. With increasing time postischemia, there was a steady increase in ICAM-1 mRNA levels in the KO mice. In wild-type mice, an increase in ICAM-1 mRNA also occurred. However, in this case there was a sharp increase in ICAM-1 mRNA at 2 h, with a decline in ICAM-1 levels at 6 and 24 h postischemia. A significant difference in ICAM-1 levels between wild-type and KO mice was observed only at 24 h postischemia (*P <0.05). However both groups did show a significant increase in mRNA expression over time.



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  		Figure 3. ICAM-1 mRNA levels in wild-type mice (closed bars) and IL-1R1/TNF-R1 knockout mice (striped bars) at 0, 2, 6, and 24 h postischemia. mRNA levels are expressed as percent relative to a baseline of 100% and corrected for gel-loading differences (P <0.05).

Postischemic VCAM-1 mRNA levels in KO and wild-type mice are shown in Figure 4 . In the KO mice, VCAM-1 mRNA levels were increased from baseline at 2, 6, and 24 h postischemia. In wild-type mice, similar increases in VCAM-1 mRNA levels were observed. VCAM-1 mRNA levels were not different between wild-type and KO mice at any postischemia period.



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  		Figure 4. VCAM-1 mRNA levels in wild-type mice (closed bars) and IL-1R1/TNF-R1 knockout mice (striped bars) at 0, 2, 6, and 24 h postischemia. mRNA levels are expressed as percent relative to a baseline of 100% and corrected for gel-loading differences.

Expression of ICAM-1 and VCAM-1 protein in postischemic tissue
Figure 5 is a representative diagram of ICAM-1 protein staining in postischemic tissue obtained from wild-type and KO mice. In normal (no IRI) wild-type kidney tissue (Fig. 5B) , there is a low level of expression of ICAM-1. At 24 h postischemia (Fig. 5C) , there is an increase in ICAM-1 expression when compared with that at 0 h. Normal KO tissue at 0 h IRI (Fig. 5E) also shows similar staining to wild-type kidney tissue. The KO 24-h-postischemic tissue (Fig. 5F) had an increase in ICAM-1 expression similar to that in the wild-type tissue.



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  		Figure 5. Up-regulation of ICAM-1 protein in wild-type and KO kidney tissue. (A) Wild-type kidney specimen with isotype control antibody staining. (B) 0-h (normal) wild-type kidney tissue stained with ICAM-1 antibody. (C) 24-h-postischemia wild-type kidney tissue stained with ICAM-1 antibody. (D) KO kidney tissue with isotype control antibody staining. (E) 0-h (normal) KO kidney tissue stained with ICAM-1 antibody. (F) 24-h-postischemia KO kidney tissue stained with ICAM-1 antibody. Magnification, x400.

VCAM-1 was found to be minimally expressed in normal wild-type and KO mouse kidney tissue (Fig. 6B and E ). After injury, there is an increase in VCAM-1 expression similar to that seen with ICAM-1 in wild-type mice (Fig. 6C) . The same was seen in the KO mouse tissue (Fig. 6F) . There was no significant difference in the amount of staining observed between wild-type and KO mouse tissue at 0 or 24 h postischemia.



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  		Figure 6. Up-regulation of VCAM-1 protein in wild-type and KO kidney tissue. (A) Wild-type kidney with isotype control antibody staining. (B) 0-h (normal) wild-type kidney tissue stained with VCAM-1 antibody. (C) 24-h-postischemia wild-type kidney tissue stained with VCAM-1 antibody. (D) KO kidney tissue with isotype control antibody staining. (E) 0-h (normal) KO kidney tissue stained with VCAM-1 antibody. (F) 24-h-postischemia KO kidney tissue stained with VCAM-1 antibody. Magnification, x400.

Renal function after IRI in KO mice
Serum creatinine levels (Fig. 7 ) were also similar between the wild-type and KO mice. Serum creatinine in both groups was increased at 24 and 48 h postischemia and then returned to baseline levels at 72 h.



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  		Figure 7. Serum creatinine levels at 24, 48, and 72 h postischemia in wild-type (•) and IL-1R1/TNF-R1 knockout mice ({circ}).

Neutrophil migration to postischemic kidney tissue
Neutrophil content of postischemic kidneys of wild-type mice was prominent at 24 h (Fig. 8 ) and then was decreased at 48 h as previously described [14 ]. KO mice had a reduced neutrophil influx at 24 h compared with that of wild-type mice. This difference was not evident at 48 h (n =4 for both). Renal neutrophils were evaluated at baseline (preischemia) and in sham-operated mice. In both groups there were <50 neutrophils per high-power field.



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  		Figure 8. Neutrophil infiltration (neutrophils/10 high-power fields) at 24 and 48 h postischemia in wild-type (closed bars) and IL-1R1/TNF-R1 KO (striped bars) mice (n =4).

Pathological assessment of postischemic renal tissue
There was significant tubular injury observed in both wild-type and KO mice 24 and 48 h after ischemia (Fig. 9 ). The pathological-damage score was similar in control and KO mice at 24 and 48 h postischemia. Sham-operated animals had no tubular injury with a pathological damage score of <1.



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  		Figure 9. Tubular necrosis scores in wild-type (closed bars) and IL-1R1/TNF-R1 KO (striped bars) mice at 24 and 48 h postischemia (n =4).


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DISCUSSION
 
Our data demonstrated that a brisk increase in expression of both ICAM-1 and VCAM-1 mRNA and protein occurred in postischemic mouse kidney tissue despite the absence of the IL-1R1 and TNF-R1 signaling pathways. Although a partial attenuation of neutrophil infiltration occurred in the IL-1/TNF KO mice at 24 h postischemia, the KO mice showed renal dysfunction and tubular necrosis comparable with that in wild-type mice.

ICAM-1 and VCAM-1 are both important leukocyte adhesion molecules that mediate leukocyte migration into areas of inflammation. Numerous studies have demonstrated an important role for ICAM-1 in renal IRI [14 15 16 , 27 28 ]. VCAM-1 has recently been seen to be important in mediating mononuclear cell infiltration into the perivasculature after kidney transplantation [29 ]. Thus, it is important to define the stimuli and pathways that induce up-regulation of these molecules in the postischemic kidney. Abundant in vitro data point to a key role for IL-1 and TNF, among other stimuli, in up-regulation of ICAM-1 [10 , 17 18 19 ]. A direct role of these cytokines in the pathogenesis of renal IRI in vivo, however, is yet to be elucidated. IL-1 has been found to mediate IRI in the heart and brain [30 , 31 ]. One study suggested that the 55-kDa TNF receptor (R1) is essential for postischemic VCAM-1 expression [32 ]. Briscoe et al. [33 ] found that endothelial VCAM-1 expression contributes to T-cell invasion at sites of inflammation and that subcutaneous TNF selectively promotes VCAM-1 expression.

Our findings that mice deficient in both the IL-1 and TNF receptor pathways can still induce ICAM-1 and VCAM-1 postischemia challenges the idea that IL-1 and TNF are essential to up-regulate these adhesion molecules in renal IRI. Thus, it is possible that IFN-{gamma} or another cytokine was responsible for the ICAM-1 and VCAM-1 up-regulation in postischemic mice. It is also possible that cytokine-independent stimuli, such as oxygen free radicals, lead to the enhanced expression of ICAM-1 and VCAM-1 [34 ]. Oxygen free radicals can directly activate nuclear factor (NF)-{kappa}B, a transcription factor that mediates formation of proinflammatory and procoagulatory proteins and regulates ICAM-1 and VCAM-1 transcription [35 , 36 ]. We acknowledge, however, that in KO mice, pathways other than those deleted may assume a disrupted pathway’s function [37 ]. It should also be noted that the absence of a specific PCR product does not absolutely ensure the absence of the protein under consideration. Nonetheless, our results are consistent with studies on Escherichia coli in mice showing that hemolytic E. coli-induced mortality is independent of IL-1 and TNF signaling. In those studies, IL-1R1- and TNF-R1-deficient mice were also used [38 ].

Studies have demonstrated a substantial protection of renal function in IRI in rats when ICAM-1 is blocked [15 , 16 ]. Recent studies of renal IRI in ICAM-1-deficient mice have confirmed a key role for ICAM-1 in this process [15 ]. Kelly et al. observed a significant attenuation in the rise in blood urea nitrogen and serum creatinine in ICAM-1-deficient mice compared with levels in controls after 30 min of bilateral pedicle clamping. They suggested that elevated TNF and IL-1 levels after ischemia and reperfusion may provide a possible mechanism of up-regulation of ICAM-1 in the postischemic tissue. In the present study, renal functional decline after IRI was similar between KO mice, possibly because mice deficient in IL-1/TNF receptors are still capable of generating an increase in ICAM-1 and VCAM-1 postischemia.

Daemen et al. [39 ] found increases in IL-10 and TNF-{alpha} after IRI. In anti-IL-10-treated rats, an enhanced proinflammatory response occurred, leading to additional impairment of renal function and neutrophil influx. By contrast, in TNF antibody-treated rats, protection from renal dysfunction was seen [39 ]. There are, however, differences in the models used in that study and in the present study, i.e., antibody blockade vs. KO mice.

We observed a modest reduction in neutrophil infiltration into the kidney in KO mice at 24 h. However, renal dysfunction and adhesion molecule protein expression at 24 h were comparable. We have not found a strong relationship between neutrophil influx and renal dysfunction in our studies, although others have. Thus the KO may have had some effect on neutrophil trafficking, but our current studies do not reveal the significance of this in terms of organ dysfunction.

In conclusion, the results of this study suggest that IL-1- and TNF-independent pathways can mediate renal adhesion molecule expression and injury postischemia. Further studies are needed to assess the role of cytokines in renal injury in vivo, which may be quite different from what in vitro data predict.


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ACKNOWLEDGEMENTS
 
M. B. was supported by a National Kidney Foundation Fellowship Award; H. R. was supported by an NIH R01 DK54770, an American Heart Association GIA, National Kidney Foundation Clinical Scientist Award, and by the Hermundslie Foundation; J. N. was supported by a Veterans Administration Merit Award.

The authors thank Dr. M. O’Donnell for critical review of the manuscript.

Received September 11, 2000; revised April 4, 2001; accepted April 5, 2001.


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