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. 2001 Jan;102(1):53–58. doi: 10.1046/j.1365-2567.2001.01141.x

Differential cellular immunolocalization of renal tumour necrosis factor-α production during ischaemia versus endotoxaemia

K K Donnahoo *, X Meng †, L Ao †, A Ayala ‡, B D Shames †, M P Cain *, A H Harken †, D R Meldrum §
PMCID: PMC1783149  PMID: 11168637

Abstract

Both renal ischaemia and endotoxaemia provoke renal dysfunction and cellular injury. Although the clinical manifestation of each insult is similar (global renal dysfunction), ischaemia and endotoxaemia induce different patterns of cellular injury. Tumour necrosis factor-α (TNF-α) has been implicated in both types of renal injury; however, it remains unknown whether differential cellular TNF-α expression accounts for these changes. We hypothesized that renal glomerular cells and tubular cells differentially express TNF-α in response to ischaemia compared with endotoxaemia. To investigate this hypothesis, male Sprague–Dawley rats were anaesthetized and exposed to various time-periods of renal ischaemia, with or without reperfusion (sham operation=negative control), or lipopolysaccharide (LPS) 0·5 mg/kg intraperitoneally (i.p.). The kidneys were harvested following renal injury, and rat TNF-α protein expression was determined (by enzyme-linked immunosorbent assay), as were TNF-α bioactivity (by WEHI-164 cell clone cytotoxicity assay) and TNF-α cellular localization (by immunohistochemistry). TNF-α protein expression and TNF-α bioactivity peaked following 1 hr of ischaemia and 2 hr of reperfusion (48 ± 11 pg/mg of protein, P < 0·05, and 12 ± 0·5 × 10−3 units/mg of protein, P < 0·05, respectively). The concentration of TNF-α increased to a similar extent following exposure to LPS; however, while TNF-α production following ischaemia-reperfusion injury localized predominantly to renal tubular epithelial cells, animals exposed to LPS demonstrated a primarily glomerular distribution of TNF-α production. Hence, the cellular localization of renal TNF-α production appears to be injury specific, i.e. renal tubular cells are the primary source of TNF-α following an ischaemic insult, whereas LPS induces glomerular TNF-α production. The cellular source of TNF-α following different insults may have therapeutic implications for targeted inhibition of TNF-α production.

Introduction

Renal ischaemia-reperfusion injury is frequently encountered in the management of surgical and urological disease. While the initial ischaemic insult may not be severe, subsequent reperfusion is believed to induce a cascade of events culminating in cellular injury and organ dysfunction. Ischaemia-induced acute tubular necrosis carries a 30% mortality rate1 and can occur during renal transplantation,2–4 partial nephrectomy,5 trauma,6 and situations that necessitate suprarenal aortic cross-clamping.7 While the mechanisms of renal ischaemia-reperfusion injury remain undefined, increasing evidence suggests that local inflammatory mediators, such as TNF-α, play an important role in the pathogenesis of this injury.2,4,8–11

Endotoxin (lipopolysaccharide [LPS]) is an intensely immunoreactive substance that is released from the outer membrane of Gram-negative bacteria following cellular disruption. When injected in large quantities, endotoxin produces the physiological alterations of septic shock, i.e. haemodynamic collapse, fever, leucocytosis and acute renal failure. The sepsis syndrome is associated with the production of many inflammatory mediators, including tumour necrosis factor-α (TNF-α).12,13 TNF-α is a proinflammatory cytokine that stimulates the production of other inflammatory mediators (i.e. interleukin-1 [IL-1], nitric oxide, platelet-activating factor and eicosanoids) and recruits and stimulates various cells within the immune system. Tracey et al. have demonstrated that TNF-α is a critical mediator of endotoxin-induced sepsis, and that inhibition of TNF-α prevents the physiological alterations and morbidity associated with LPS administration.12,13

TNF-α is produced by the kidney in response to LPS and its production is known to cause direct renal cytotoxicity (apoptosis), glomerular fibrin deposition, cellular infiltration and eventual renal failure.14–19 The primary source of renal TNF-α has traditionally been considered to be the infiltrating peripheral monocyte. TNF-α was originally described as an LPS-induced macrophage product and the abundance of research on TNF-α has focused on this cellular source. In the macrophage, the signalling cascade leading to TNF-α production has been well defined. LPS binds to CD14, a macrophage-specific cell surface receptor, which in turn activates a series of protein kinases. Activation of the transcription factor nuclear factor κB (NFκB) then ensues, leading to an increase in TNF-α gene transcription.20–23

Accumulating evidence now suggests that resident renal cells are also capable of producing TNF-α.24–27 Mesangial cells cultured from rat glomeruli produce TNF-α in response to bacterial LPS, even after the rats have been deprived of bone marrow-derived cells by whole body irradiation.24,27 Furthermore, immunocytochemical techniques have localized TNF-α production, following LPS stimulation, to glomerular mesangial cells.26 While renal TNF-α production has been clearly demonstrated following LPS exposure and ischaemia-reperfusion injury,28 it remains unknown which cell type(s) are responsible and whether the cellular immunolocalization of TNF-α production varies based on the type of renal insult. The purposes of this study were therefore to:

  1. Determine the time-course of renal TNF-α protein expression following renal ischaemia and reperfusion.

  2. Measure TNF-α bioactivity following renal ischaemia and reperfusion.

  3. Determine and compare the renal cellular localization of TNF-α production following ischaemia-reperfusion injury and exposure to LPS.

Materials and methods

Animals

Male Sprague–Dawley rats weighing 250–300 g were acclimatized and maintained on a standard pellet diet for 1 week prior to the initiation of experiments. Animals were anaesthetized intraperitoneally (i.p.) with sodium pentobarbital, 30 mg/kg, prior to the experiments. The animal protocol was reviewed and approved by the Animal Care and Research Committee of the University of Colorado Health Sciences Center. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals (NIH publication no. 85–23, revised 1985).

Experimental groups

The left renal pedicle was isolated and occluded for periods of 30 or 60 min. Reperfusion was then allowed to occur for 0, 1, 2 or 4 hr. Sham animals underwent identical surgical treatment, including isolation of the renal pedicle; however, subsequent occlusion of the pedicle was not performed. Following reperfusion, the kidneys were removed and frozen in liquid nitrogen. The samples were stored at −70° until further testing was performed. All animals were killed following completion of the experiment. The animals (n = 5–7 per group) were divided into the following experimental groups:

  1. Animals undergoing a sham operation (negative control).

  2. Animals receiving a sublethal dose of LPS (0·5 mg/kg i.p.) 2 hr prior to kidney removal.

  3. Animals receiving 30 min of ischaemia alone.

  4. Animals receiving 60 min of ischaemia alone.

  5. Animals receiving 60 min of ischaemia followed by 1 hr of reperfusion.

  6. Animals receiving 60 min of ischaemia followed by 2 hr of reperfusion.

  7. Animals receiving 60 min of ischaemia followed by 4 hr of reperfusion.

Tissue homogenization

A portion of each kidney was homogenized for the enzyme-linked immunosorbent assay (ELISA) and TNF-α bioactivity assay. Homogenization was performed after the samples had been diluted in 4 vol. of homogenate buffer: 10 mm HEPES (pH 7·9), 10 mm KCl, 0·1 mm EGTA, 1 mm dithiothreitol (DTT), and Complete Protease Inhibitor tabs (Boehringer Mannheim, Indianapolis, IN), using a vertishear tissue homogenizer. Renal homogenates were centrifuged at 3000 g for 15 min, the total protein concentration of the supernatant was quantified using the Lowry assay and supernatants were stored at −70° until the TNF bioactivity and ELISA assays were performed.

TNF-α protein expression and bioactivity

Renal homogenate TNF-α protein content and bioactivity were determined using ELISA and the WEHI-164 clone cytotoxicity assay, respectively. The ELISA was performed by adding 100 µl of each sample (tested in duplicate) to wells of a 96-well plate of a commercially available rat TNF-α ELISA kit (R&D Systems, Inc., Minneapolis, MN). According to the manufacturer, the ELISA is highly specific for rat TNF-α with a detection limit of 15 pg/ml. The ELISA was performed according to the manufacturer's instructions and the results were calibrated against a standard concentration of rat TNF-α provided in the kit. Final results were expressed as pg of TNF-α per mg of protein.

TNF-α bioactivity in each kidney sample was determined utilizing the WEHI-164 cell clone (clone 13) cytotoxicity assay, as previously described.29,30 The assay is routinely sensitive to a lower limit of 0·008 units of mouse TNF/ml. All samples were tested in duplicate and the standard curve in triplicate. The definition of a ‘unit of cytokine activity’ is defined by the manufacturer (Pharmingen Inc., San Diego, CA) as the amount of material required to stimulate a half-maximal response at cytokine saturation. The conversion for units under these conditions is: 1 unit=1 pg of mouse TNF protein. Final results were expressed as units of TNF-α activity per mg of total protein.

Immunolocalization of TNF-α

Immunolocalization of renal TNF-α production was determined using sections of renal tissue obtained from sham-operated animals, animals exposed to LPS and animals exposed to 60 min of ischaemia and 2 hr of reperfusion (time-point of maximal TNF-α production). Transverse 5-µm cryosections were prepared using a cryostat [2800 Frigocut E., Reichert-Jung (now Leica), Solms, Germany] and collected on slides coated with poly-l-lysine. All sections were fixed for 10 min in 70% acetone/30% methanol at −20°. Normal goat serum was applied as a blocking agent and the slides were washed in phosphate-buffered saline (PBS) three times (3 min each wash). Sections were then incubated with diluted primary antibody (rabbit anti-human TNF-α polyclonal antibody: 1 : 200 dilution; Genzyme, Cambridge, MA) for 1 hr. The sections were washed with PBS and incubated with Cy-3-conjugated goat anti-rabbit immunoglobulin G (IgG) for 45 min. After rewashing with PBS, the nuclei were stained with bis-Benzimide (10 µg/ml in PBS) for 30 seconds and the slides were washed with PBS three times (2 min each wash). Cell membranes were counterstained with Oregon Green 488-labelled wheatgerm agglutinin (1 : 100 dilution; Molecular Probes, Eugene, OR) for 30 min and washed with PBS three times. The slides were mounted with a glycerol-based antiquenching agent, o-phenylene diamine-d : HCl, and stored at −4°. To test for non-specific fluorescence, adjacent sections from each experimental group were incubated with non-immune purified rabbit IgG instead of the primary antibody. Non-specific fluorescence was digitally subtracted and sections were photographed using a confocal microscope.

Statistical analysis

Data are presented as mean values±standard error of the mean (SEM). Differences at the 95% confidence level were considered significant. The experimental groups were compared using analysis of variance (anova) with posthoc Bonferroni–Dunn (StatView 4.0; Berkeley, CA).

Results

Determination of rat TNF-α protein expression and bioactivity

Renal homogenates were assayed for rat TNF-α protein content and bioactivity following treatment with LPS and varying times of ischaemia and reperfusion. Untreated and sham-operated animals demonstrated low levels of TNF-α expression, at 11 ± 1·2 and 20·4 ± 1·2 pg/mg of protein, respectively (Fig. 1). TNF-α levels were markedly elevated in animals exposed to LPS (0·5 mg/kg i.p.) at 59·4 ± 9·3 pg/mg of protein (P < 0·05 versus sham). There was no appreciable increase in TNF-α levels compared with sham-operated animals following 30 min (19 ± 3 pg/mg of protein) or 60 min (24 ± 4·7 pg/mg of protein) of isolated renal ischaemia; however, TNF-α levels increased significantly (P < 0·05 versus sham) when the animals were exposed to 1 hr of ischaemia followed by 1 hr of reperfusion (42 ± 2 pg/mg of protein). TNF-α expression peaked after 2 hr of reperfusion (48 ± 11 pg/mg of protein) and declined following 4 hr of reperfusion (16·2 ± 1·2 pg/mg of protein).

Figure 1.

Figure 1

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Time-course of renal tissue tumour necrosis factor-α (TNF-α) protein expression during ischaemia and reperfusion. Ischaemia alone did not result in significant TNF-α protein expression; however, 1 hr of ischaemia followed by 1 or 2 hr of reperfusion induced a significant increase in TNF-α protein expression. TNF-α protein levels returned to baseline after 4 hr of reperfusion. *P < 0·05.

Increases in TNF-α bioactivity paralleled the observed increases in TNF-α protein expression (Fig. 2). TNF-α bioactivity was minimal among sham-treated animals (2·7 ± 1·1 × 10−3 units/mg of protein). In contrast, cytotoxicity levels increased significantly (P < 0·05) in the LPS (20 ± 3·7 × 10−3 units/mg of protein), 1 hr ischaemia/1 hr reperfusion (8·1 ± 2·5 × 10−3 units/mg of protein), and 1 hr ischaemia/2 hr reperfusion (12 ± 0·5 × 10−3 units/mg of protein) treatment groups.

Figure 2.

Figure 2

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Time-course of renal tissue tumour necrosis factor-α (TNF-α) bioactivity during ischaemia and reperfusion. TNF-α bioactivity increased significantly after 1 hr of ischaemia followed by 1 or 2 hr of reperfusion. After 4 hr of reperfusion, TNF-α bioactivity returned to baseline. *P < 0·05.

Immunolocalization of TNF-α

In order to localize the cellular production of TNF-α, renal samples were obtained from animals exposed to a sham operation, LPS, or 1 hr of ischaemia/2 hr of reperfusion (the time-point of maximal TNF-α production). Sections of each renal sample were stained for TNF-α using immunohistochemical techniques. Only trace amounts of TNF-α were detected in samples obtained from the sham-operated animals (Fig. 3a). In contrast, significant amounts of TNF-α were present in animals exposed to either LPS or ischaemia-reperfusion injury (Fig. 3b, 3c). TNF-α production localized primarily to glomerular cells following LPS exposure and to renal tubular cells following ischaemia-reperfusion injury.

Figure 3.

Figure 3

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Immunolocalization of tumour necrosis factor-α (TNF-α) in rat kidney following lipopolysaccharide (LPS) or ischaemia-reperfusion injury (5-µm sections, magnification ×600). (a) Renal tissue obtained from a sham-operated animal. Cell nuclei are stained blue and cell membranes counterstained green. No TNF-α is present (red stain). (b) Renal tissue obtained following LPS exposure. TNF-α localizes primarily to renal glomerular cells. (c) Renal tissue obtained following ischaemia-reperfusion injury. TNF-α localizes primarily to renal tubular cells. G, glomerulus; T, tubule.

Discussion

Significant cellular injury and renal dysfunction can occur following short periods of renal ischaemia.3,17,31 While the exact mechanisms of ischaemia-reperfusion injury remain unclear, accumulating evidence implicates inflammatory mediators in the pathogenesis of this injury.3,4,28,32,33 TNF-α is a proinflammatory cytokine capable of inducing renal dysfunction. Infusion of TNF-α into rabbits induces glomerular endothelial damage, neutrophil infiltration, fibrin deposition and renal failure.14 The mechanisms of TNF-α-induced renal injury are multiple. TNF-α induces renal cellular apoptosis and reduces glomerular blood flow and glomerular filtration rate by stimulating the production of a variety of vasoactive mediators (i.e. platelet-activating factor, endothelin-1, prostaglandins, nitric oxide).15,18,34–36 TNF-α also stimulates the production of other inflammatory mediators, including reactive oxygen species and IL-1, which generate an increase in glomerular permeability and contribute to further cellular and organ dysfunction.37–40 Thus, early local TNF-α production has both paracrine and autocrine effects, which can contribute to renal injury.

This study demonstrates that renal ischaemia-reperfusion injury induces an increase in renal tissue TNF-α protein content and TNF-α bioactivity, corroborating our previous observations.28 It has been well established that reperfusion of ischemic tissue leads to the production of oxygen free radicals, including hydrogen peroxide. These reactive oxygen species can stimulate a cascade of events leading to inflammatory cytokine production and cellular apoptosis. Hydrogen peroxide directly activates NFκB, a transcription factor that up-regulates TNF-α gene transcription.9,41–45 Hydrogen peroxide can also directly activate p38 mitogen-activated protein kinase (p38 MAP kinase), a stress-induced protein kinase, which is important for NFκB activation and subsequent TNF-α production. We demonstrated in the present study that 60 min of renal ischaemia followed by 60 min of reperfusion were sufficient to induce an increase in TNF-α protein content and TNF-α bioactivity.

In addition to ischaemia-reperfusion injury, TNF-α has been implicated in a variety of other inflammatory diseases of the kidney, including autoimmune lupus nephritis, glomerulonephritis, diabetic nephropathy and septic acute renal failure.14,46–50 The cellular and molecular responses to these various noxious stimuli all result in an inflammatory cell infiltrate and proinflammatory mediator production. While TNF-α has been well characterized as a secretory product of the macrophage, evidence suggests that it can also be produced locally by glomerular mesangial cells in response to LPS.24,26,27 It is unclear what role locally produced TNF-α has in the pathogenesis of inflammatory renal disease, and attempts to localize TNF-α production have yielded mixed results in the literature. Using immunohistochemical techniques, Diamond & Pesek demonstrated that the primary source of TNF-α following acute aminonucleoside-induced nephrosis is the infiltrating macrophage.51 In contrast, other investigators have demonstrated TNF-α production from resident glomerular cells in macrophage-depleted animal models.24,52

Our immunohistochemical data confirm that TNF-α is produced by resident renal cells in response to noxious stimuli and constitutes the initial demonstration that differential cellular TNF-α immunolocalization occurs following ischaemia compared with endotoxaemia. While minimal TNF-α staining was present in sham-operated animals, a significant increase in TNF-α was detected after renal ischaemia-reperfusion injury and upon renal exposure to LPS (Fig. 3a, 3b, 3c). Interestingly, the cellular localization of TNF-α production differed significantly between these two models of renal injury. Ischaemia-reperfusion injury induced renal tubular cell production of TNF-α and, to a much lesser extent, glomerular cell production of TNF-α. In contrast, animals exposed to LPS demonstrated a primarily glomerular distribution of TNF-α production. These data support previous observations that glomerular mesangial cells produce TNF-α in response to LPS24,26,27 and, furthermore, demonstrate an injury-specific pattern of TNF-α production. This pattern of TNF-α production may represent variations in cell sensitivity to oxidants or variations in the expression of cell surface receptors (i.e. CD14).

Renal ischaemia-reperfusion injury is encountered in many surgical and urological clinical situations uniquely suited to pretreatment, i.e. kidney transplantation, partial nephrectomy, renal artery angioplasty and trauma. We have demonstrated that the level of TNF-α is increased in renal tubular cells following ischaemia-reperfusion injury, and that the cellular localization of renal TNF-α production is injury specific. As the role of TNF-α in inflammatory renal injury is defined, this injury-specific pattern of TNF-α production may become therapeutically important to the development of targeted anti-TNF-α treatment strategies.

Acknowledgments

This research was supported by the National Institutes of Health grants GM08135, GM49222, and a National Research Service Award.

References

  • 1.Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med. 1998;128:194. doi: 10.7326/0003-4819-128-3-199802010-00005. [DOI] [PubMed] [Google Scholar]
  • 2.Takada M, Nadeau KC, Shaw GD, Tilney NL. Prevention of late renal changes after initial ischemia/reperfusion injury by blocking early selectin binding. Transplantation. 1997;64:1520. doi: 10.1097/00007890-199712150-00003. [DOI] [PubMed] [Google Scholar]
  • 3.Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-α adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest. 1997;99:2682. doi: 10.1172/JCI119457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Garcia-Criado FJ, Eleno N, Santos-Benito F, et al. Protective effect of exogenous nitric oxide on the renal function and inflammatory response in a model of ischemia-reperfusion. Transplantation. 1998;66:982. doi: 10.1097/00007890-199810270-00003. [DOI] [PubMed] [Google Scholar]
  • 5.Gschwend JE, Petriconi RD, Maier S, Kleinschmidt K, Hautmann RE. Continuous in situ cold perfusion with histidine tryptophan ketoglutarate solution in nephron sparing surgery for renal tumors. J Urol. 1995;154:1307. [PubMed] [Google Scholar]
  • 6.Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998;273:4135. doi: 10.1074/jbc.273.7.4135. [DOI] [PubMed] [Google Scholar]
  • 7.Kazmers A, Jacobs L, Perkins A. The impact of complications after vascular surgery in Veterans Affairs Medical Centers. J Surg Res. 1997;67:62. doi: 10.1006/jsre.1996.4946. 10.1006/jsre.1996.4946. [DOI] [PubMed] [Google Scholar]
  • 8.Meldrum DR, Shenkar R, Sheridan BC, Cain BS, Abraham E, Harken AH. Hemorrhage activates myocardial NFκB and increases tumor necrosis factor in the heart. J Mol Cell Cardiol. 1997;29:2849. doi: 10.1006/jmcc.1997.0506. 10.1006/jmcc.1997.0506. [DOI] [PubMed] [Google Scholar]
  • 9.Meldrum DR. Tumor necrosis factor in the heart (Review) Am J Physiol. 1998;274:R577. doi: 10.1152/ajpregu.1998.274.3.R577. [DOI] [PubMed] [Google Scholar]
  • 10.Chandraker A, Takada M, Nadeau KC, Peach R, Tilney NL, Sayegh MH. CD28-b7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury. Kidney Int. 1997;52:1678. doi: 10.1038/ki.1997.502. [DOI] [PubMed] [Google Scholar]
  • 11.Combe C, Burton CJ, Dufourco P, Weston S, Horsburgh T, Walls J, Harris KP. Hypoxia induces intercellular adhesion molecule-1 on cultured human tubular cells. Kidney Int. 1997;51:1703. doi: 10.1038/ki.1997.235. [DOI] [PubMed] [Google Scholar]
  • 12.Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science. 1987;234:470. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  • 13.Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature. 1987;330:662. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  • 14.Bertani T, Abbate M, Zoja C, Corna D, Perico N, Ghezzi P, Remuzzi G. Tumor necrosis factor induces glomerular damage in the rabbit. Am J Pathol. 1989;134:419. [PMC free article] [PubMed] [Google Scholar]
  • 15.Soler PA, Mullin JM, Knudsen KA, Marano CW. Tissue remodeling during tumor necrosis factor-induced apoptosis in LLC-PK1 renal epithelial cells. Am J Physiol. 1996;270:F869. doi: 10.1152/ajprenal.1996.270.5.F869. [DOI] [PubMed] [Google Scholar]
  • 16.Donnahoo KK, Shames BD, Harken AH, Meldrum DR. The role of tumor necrosis factor in renal ischemia-reperfusion injury (Review) J Urol. 1999;162:196. doi: 10.1097/00005392-199907000-00068. [DOI] [PubMed] [Google Scholar]
  • 17.Lieberthal W, Koh JS, Levine JS. Necrosis and apoptosis in acute renal failure. Semin Nephrol. 1998;18:505. [PubMed] [Google Scholar]
  • 18.Baud L, Ardaillou R. Tumor necrosis factor in renal injury. Miner Electrolyte Metab. 1995;21:336. [PubMed] [Google Scholar]
  • 19.Brady HR, Spertini O, Jimenez W, Brenner BM, Marsden PA, Tedder TF. Neutrophils, monocytes, and lymphocytes bind to cytokine-α activated kidney glomerular endothelial cells through l-selectin (LAM-1) in vitro. J Immunol. 1992;149:2437. [PubMed] [Google Scholar]
  • 20.Sweet MJ, Hume DA. Endotoxin signal transduction in macrophages. J Leukoc Biol. 1996;60:8. doi: 10.1002/jlb.60.1.8. [DOI] [PubMed] [Google Scholar]
  • 21.Han H, Lee JD, Tobias PS, Ulevitch RJ. Endotoxin induces rapid tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem. 1993;268:25009. [PubMed] [Google Scholar]
  • 22.Sanghera JS, Weinstein SL, Aluwalia M, Girn J, Pelech SL. Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. J Immunol. 1996;156:4457. [PubMed] [Google Scholar]
  • 23.Lee JC, Laydon JT, McDonnel PC, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739. doi: 10.1038/372739a0. [DOI] [PubMed] [Google Scholar]
  • 24.Fouqueray B, Philippe C, Herbelin A, Perez J, Ardaillou R, Baud L. Cytokine formation within rat glomeruli during experimental endotoxemia. J Am Soc Nephrol. 1993;3:1783. doi: 10.1681/ASN.V3111783. [DOI] [PubMed] [Google Scholar]
  • 25.Giroir BP, Johnson JH, Brown T, Allen GL, Beutler B. The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia. J Clin Invest. 1992;90:693. doi: 10.1172/JCI115939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kita T, Tanaka N, Nagano T. The immunocytochemical localization of tumor necrosis factor and leukotriene in the rat kidney after treatment with lipopolysaccharide. Int J Exp Pathol. 1993;74:471. [PMC free article] [PubMed] [Google Scholar]
  • 27.Baud L, Oudinet J-P, Bens M, Noe L, Peraldi M-N, Rondeau E, Etienne J, Ardaillou R. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35:1111. doi: 10.1038/ki.1989.98. [DOI] [PubMed] [Google Scholar]
  • 28.Donnahoo K, Meng X, Ayala A, Cain M, Harken A, Meldrum D. Early kidney TNF-α expression mediates neutrophil infiltration and injury following isolated renal ischemia-reperfusion. Am J Physiol. 1999;277:R922. doi: 10.1152/ajpregu.1999.277.3.R922. [DOI] [PubMed] [Google Scholar]
  • 29.Ayala A, Perrin MM, Meldrum DR, Ertel W, Chaudry IH. Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin. Cytokine. 1990;2:170. doi: 10.1016/1043-4666(90)90012-i. [DOI] [PubMed] [Google Scholar]
  • 30.Ayala A, Perrin MM, Wang P, Ertel W, Chaudry IH. Hemorrhage induces enhanced kupffer cell cytoxicity while decreasing peritoneal or splenic macrophage capacity. J Immunol. 1991;147:4147. [PubMed] [Google Scholar]
  • 31.Schumer M, Colombel MC, Sawczuk IS, et al. Morphologic, biochemical, and molecular evidence of apoptosis during the reperfusion phase after brief periods of renal ischemia. Am J Pathol. 1992;140:831. [PMC free article] [PubMed] [Google Scholar]
  • 32.Gurevitch J, Frolkis I, Yuhas Y, Paz Y, Matsa M, Mohr R, Yakirevich V. Tumor necrosis factor-α is released from the isolated heart undergoing ischemia and reperfusion. J Am Coll Cardiol. 1996;28:247. doi: 10.1016/0735-1097(96)00105-2. 10.1016/0735-1097(96)00105-2. [DOI] [PubMed] [Google Scholar]
  • 33.Seekamp A, Warren JS, Remick DG, Till GO, Ward PA. Requirements for tumor necrosis factor-α and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury. Am J Pathol. 1993;143:453. [PMC free article] [PubMed] [Google Scholar]
  • 34.Gomez-Chiarri M, Ortiz A, Lerma JL, Lopez-Αrmada MJ, Mampaso F, Gonzalez E, Egido J. Involvement of tumor necrosis factor-α and platelet activating factor in the pathogenesis of experimental nephrosis in rats. Lab Invest. 1994;70:449. [PubMed] [Google Scholar]
  • 35.Kohan DE. Role of endothelin and tumor necrosis factor in the renal response to sepsis. Nephrol Dial Transplant. 1994;9:73. [PubMed] [Google Scholar]
  • 36.Baud L, Perez J, Friedlander G, Ardaillou R. Tumor necrosis factor stimulates prostaglandin production and cylic AMP levels in rat cultured mesangial cells. FEBS Lett. 1988;239:50. doi: 10.1016/0014-5793(88)80543-x. [DOI] [PubMed] [Google Scholar]
  • 37.Dinarello CA, Cannon JG, Wolff SM, et al. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of IL-1. J Exp Med. 1986;163:1433. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Radeke HH, Meier B, Topley N, Floge J, Habermehl GG, Resch K. Interleukin-1 and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells. Kidney Int. 1990;37:767. doi: 10.1038/ki.1990.44. [DOI] [PubMed] [Google Scholar]
  • 39.Mullin JM, Laughlin KV, Marano CW, Russo LM, Soler AP. Modulation of tumor necrosis factor-induced increase in renal (LLC-PK1) transepithelial permeability. Am J Physiol. 1992;263:F915. doi: 10.1152/ajprenal.1992.263.5.F915. [DOI] [PubMed] [Google Scholar]
  • 40.McCarthy ET, Sharma R, Li JZ, Sarin VJ. TNF increases albumin permeability through the generation of superoxide. J Am Soc Nephrol. 1993;4:620. doi: 10.1681/ASN.V93433. [DOI] [PubMed] [Google Scholar]
  • 41.Meldrum DR, Dinarello CA, Cleveland JC, Cain BS, Shames BD, Meng X, Harken AH. Hydrogen peroxide induces tumor necrosis factor-alpha mediated cardiac injury by a P38 mitogen activated protein kinase dependent mechanism. Surgery. 1998;124:291. doi: 10.1067/msy.1998.90570. [DOI] [PubMed] [Google Scholar]
  • 42.Yin T, Sandhu G, Wolfgang CD, Burrier A, Webb RL, Rigel DF, Hai T, Whelan J. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem. 1997;272:19943. doi: 10.1074/jbc.272.32.19943. [DOI] [PubMed] [Google Scholar]
  • 43.Knight RJ, Buxton DB. Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat heart. Biochem Biophys Res Commun. 1996;218:83. doi: 10.1006/bbrc.1996.0016. 10.1006/bbrc.1996.0016. [DOI] [PubMed] [Google Scholar]
  • 44.Guyton KZ, Liu Y, Gorospe M, Xu Q, Holbrook NJ. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem. 1996;271:4138. doi: 10.1074/jbc.271.8.4138. [DOI] [PubMed] [Google Scholar]
  • 45.Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  • 46.Azuma H, Nadeau K, Takada M, Mackenzie HS, Tilney NL. Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney. Transplantation. 1997;64:190. doi: 10.1097/00007890-199707270-00002. [DOI] [PubMed] [Google Scholar]
  • 47.Boswell JM, Yui MA, Burt DW, Kelley VE. Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis. J Immunol. 1998;141:3050. [PubMed] [Google Scholar]
  • 48.Brennan DC, Yui MA, Wuthrich RP, Kelley VF. Tumor necrosis factor and interleukin 1 in New Zealand black/white mice. Enhanced gene expression and acceleration of renal injury. J Immunol. 1989;143:3470. [PubMed] [Google Scholar]
  • 49.Camussi G, Tetta C, Bussolino F, Turello E, Brentjens J, Montrucchio G, Andres G. Effect of leukocyte stimulation on rabbit immune complex glomerulonephritis. Kidney Int. 1990;38:1047. doi: 10.1038/ki.1990.311. [DOI] [PubMed] [Google Scholar]
  • 50.Nakamura T, Fukui M, Ebihara I, Osada S, Nagaoka I, Tomino Y, Koide H. mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes. 1993;42:450. doi: 10.2337/diab.42.3.450. [DOI] [PubMed] [Google Scholar]
  • 51.Diamond JR, Pesek I. Glomerular tumor necrosis factor and interleukin 1 during acute aminonucleoside nephrosis: an immunohistochemical study. Lab Invest. 1991;64:21. [PubMed] [Google Scholar]
  • 52.Xia Y, Feng L, Yoshimura T, Wilson CB. LPS-induced MCP-1, IL-1β, and TNF-α mRNA expression in isolated erythrocyte-perfused rat kidney. Am J Physiol. 1993;264:F774. doi: 10.1152/ajprenal.1993.264.5.F774. [DOI] [PubMed] [Google Scholar]

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