Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-α produced by renal parenchymal cells
2007; Elsevier BV; Volume: 72; Issue: 1 Linguagem: Inglês
10.1038/sj.ki.5002242
ISSN1523-1755
AutoresBing‐bing Zhang, Ganesan Ramesh, Christopher C. Norbury, William Reeves,
Tópico(s)Acute Kidney Injury Research
ResumoCisplatin is a chemotherapeutic agent that induces tumor necrosis factor-α (TNF-α) production in many cell types with unfortunate renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrow-derived immune cells to the pathogenesis of cisplatin-induced renal injury in vivo. To do this we created chimeric mice in which the bone marrow was ablated and replaced with donor bone marrow cells from wild-type or from TNF-α knockout mice. Six weeks after reconstitution, the chimeric mice were treated with cisplatin and renal structural and functional parameters were measured. Chimeras with kidneys of wild-type animals all developed significant renal failure after 72 h of cisplatin treatment regardless of the immune cell source. Chimeras with kidneys of TNF-α knockout mice showed significantly less renal dysfunction (blood urea nitrogen, serum creatinine, and glomerular filtration rate), renal histologic injury, and serum TNF-α levels; again regardless of the immune cell source. Urinary excretion of several proinflammatory cytokines was lower in the wild-type bone marrow-knockout kidney chimera mouse than in wild-type background mice. Our results indicate that a substantial portion of circulating and urinary TNF-α is derived from nonimmune cells after cisplatin administration. We conclude that the production of TNF-α by renal parenchymal cells, rather than by bone marrow-derived infiltrating immune cells, is responsible for cisplatin-induced nephrotoxicity. Cisplatin is a chemotherapeutic agent that induces tumor necrosis factor-α (TNF-α) production in many cell types with unfortunate renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrow-derived immune cells to the pathogenesis of cisplatin-induced renal injury in vivo. To do this we created chimeric mice in which the bone marrow was ablated and replaced with donor bone marrow cells from wild-type or from TNF-α knockout mice. Six weeks after reconstitution, the chimeric mice were treated with cisplatin and renal structural and functional parameters were measured. Chimeras with kidneys of wild-type animals all developed significant renal failure after 72 h of cisplatin treatment regardless of the immune cell source. Chimeras with kidneys of TNF-α knockout mice showed significantly less renal dysfunction (blood urea nitrogen, serum creatinine, and glomerular filtration rate), renal histologic injury, and serum TNF-α levels; again regardless of the immune cell source. Urinary excretion of several proinflammatory cytokines was lower in the wild-type bone marrow-knockout kidney chimera mouse than in wild-type background mice. Our results indicate that a substantial portion of circulating and urinary TNF-α is derived from nonimmune cells after cisplatin administration. We conclude that the production of TNF-α by renal parenchymal cells, rather than by bone marrow-derived infiltrating immune cells, is responsible for cisplatin-induced nephrotoxicity. Cisplatin is a common and effective chemotherapeutic agent for the treatment of many types of cancer. An unfortunate consequence of cisplatin treatment is renal toxicity which affects 25–35% of treated patients.1Lebwohl D. Canetta R. Clinical development of platinum complexes in cancer therapy: an historical perspective and an update.Eur J Cancer. 1998; 34: 1522-1534Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar Studies from our laboratory2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar,3Ramesh G. Reeves W.B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol: Renal Physiol. 2003; 54: F610-F618Crossref Scopus (219) Google Scholar and others4Deng J. Kohda Y. Chiao H. et al.Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury.Kidney Int. 2001; 60: 2118-2128Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar,5Tsuruya K. Ninomiya T. Tokumoto M. et al.Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death.Kidney Int. 2003; 63: 72-82Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar have demonstrated that tumor necrosis factor-α (TNF-α) production is increased in cisplatin toxicity. We also demonstrated that TNF-α plays a pathogenic role in stimulating cytokine and chemokine expression in the kidney and in producing acute renal failure.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar Specifically, genetic deletion of TNF-α or pharmacologic inhibition of TNF-α action reduced the expression of inflammatory cytokines and chemokines (e.g. TNF-α, monocyte chemotactic protein-1 (MCP-1), and regulated upon activation normal T-cell expressed and secreted (RANTES)) and preserved renal function after cisplatin injection. These effects of TNF-α were determined to be mediated via the TNFR2 receptor subtype.3Ramesh G. Reeves W.B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol: Renal Physiol. 2003; 54: F610-F618Crossref Scopus (219) Google Scholar Although these studies indicated that TNF-α gene expression and protein content within the kidney increased after cisplatin administration, the source of the TNF-α which was responsible for renal injury was unclear. TNF-α is produced by a broad range of tissues and cells, including immune cells and intrinsic renal cells, such as mesangial cells,6Baud L. Oudinet J. Bens M. et al.Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide.Kidney Int. 1989; 35: 1111-1118Abstract Full Text PDF PubMed Scopus (185) Google Scholar glomerular7Neale T. Ruger B. Macaulay H. et al.Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy.Am J Pathol. 1995; 146: 1444-1454PubMed Google Scholar,8Noiri E. Kuwata S. Nosaka K. et al.Tumor necrosis factor-alpha mRNA expression in lipopolysaccharide- stimulated rat kidney. Chronological analysis of localization.Am J Pathol. 1994; 144: 1159-1166PubMed Google Scholar and tubular epithelial cells,9Ramesh G. Reeves W.B. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice.Am J Physiol Renal Physiol. 2005; 289: F166-174Crossref PubMed Scopus (212) Google Scholar, 10Jevnikar A. Brennan D. Singer G. et al.Stimulated kidney tubular epithelial cells express membrane associated and secreted TNFa.Kidney Int. 1991; 40: 203-211Abstract Full Text PDF PubMed Scopus (143) Google Scholar, 11Wuthrich R.P. Glimcher L.H. Yui M.A. et al.MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells.Kidney Int. 1990; 37: 783-792Abstract Full Text PDF PubMed Scopus (233) Google Scholar and endothelial cells.12Albaugh G. Kann B. Strande L. et al.Nicotine induces endothelial TNF-alpha expression, which mediates growth retardation in vitro.J Surg Res. 2001; 99: 381-384Abstract Full Text PDF PubMed Scopus (29) Google Scholar,13Eissner G. Lindner H. Konur A. et al.Naive monocytes can trigger transendothelial migration of peripheral blood cells through the induction of endothelial tumour necrosis factor-alpha.Scand J Immunol. 2000; 51: 251-261Crossref PubMed Scopus (6) Google Scholar The extent to which infiltrating immune cells and intrinsic renal cells produce TNF-α and mediate nephrotoxicity in response to cisplatin is not known. Therefore, the purpose of the present study was to determine the relative contribution of TNF-α produced by renal parenchymal cells vs leukocytes in mediating cisplatin-induced renal injury in vivo. We created chimeric mice in which TNF-α can be produced by either resident kidney cells or circulating immune cells. We evaluated kidney function, histology, and cytokine expression in these chimeric mice following cisplatin administration. The results indicate the local production of TNF-α by resident kidney cells is crucial in cisplatin-induced nephrotoxicity. Chimeric mice were created to examine the differential role of leukocyte-derived versus kidney-derived TNF-α in the pathogenesis of cisplatin nephrotoxicity. First, it was important to show that the bone marrow transplantation procedure resulted in a high degree of chimerism, did not alter the distribution of circulating leukocyte subtypes, and did not impact the ability of circulating immune cells to produce TNF-α (Figure 1). To determine the extent of chimerism, enhanced green fluorescent protein (EGFP) was used as a marker of the donor bone marrow. Figure 1a shows the results of flow cytometry of peripheral blood obtained from nontransplanted EGFP-expressing transgenic mice and from chimeric mice in which EGFP bone marrow was transplanted into non-EGFP expressing C57BL6 mice. The frequency of EGFP-positive cells in the two sets of mice was virtually identical, indicating almost complete replacement (>98%) of the recipient circulating leukocytes by donor cells. As studies have indicated a role for neutrophils and B and T lymphocytes in the development of acute renal failure, the effect of bone marrow transplantation on the distribution of various subtypes of peripheral blood leukocytes was determined. Two-color flow cytometry was performed on leukocytes stained for a common leukocyte antigen (CD45) and markers for CD4 and CD8 lymphocytes, B cells, macrophages, NK cells, and neutrophils. The distribution of each subtype, as a percentage of CD45-positive cells, was the same in nontransplanted and chimeric mice (Table 1). Next, intracellular cytokine staining was used to determine the ability of transplanted immune cells to produce TNF-α. Peripheral blood leukocytes were obtained from either EGFP-expressing transgenic mice or TNF-α knockout mice that had been transplanted with EGFP bone marrow 6 weeks earlier (Figure 1b). Cells were stimulated in vitro to produce TNF-α, fixed, permeabilized, and stained with TNF-α antibodies as described in the Materials and Methods. Flow cytometry was used to determine the levels of EGFP expression and TNF-α content. As shown in Figure 1b and c, approximately 26% of circulating EGFP-positive cells in both sets of mice stained positive for TNF-α. This result indicates that the bone marrow transplantation procedure itself did not impair TNF-α production by the donor immune cells.Table 1Distribution of circulating leukocytes in nontransplanted and chimeric miceCD4CD8B cellsMacrophagesNK cellsNeutrophilsWT (C57BL6)10.9±1.610.2±2.651.3±9.10.9±0.51.5±0.412.5±7.7WT → WT13.0±1.49.8±1.459.3±6.50.6±0.21.0±0.38.1±4.1P=NSP=NSP=NSP=NSP=NSP=NSANOVA, analysis of variance; NK cells, natural killer cells; NS, not significant.All data are %±s.d. of CD45(+) cells. N=3 in each group. P-values were calculated by ANOVA. Open table in a new tab ANOVA, analysis of variance; NK cells, natural killer cells; NS, not significant. All data are %±s.d. of CD45(+) cells. N=3 in each group. P-values were calculated by ANOVA. Next, bone marrow chimeric mice were treated with cisplatin (20 mg/kg body weight) or saline and assessed for renal dysfunction. As shown in Figure 2, WT → WT chimeric mice developed severe renal failure between 48 and 72 h. The degree of renal dysfunction at 72 h (BUN 140±10 mg/dl, and creatinine 1.12±0.10 mg/dl) was similar to what we have observed in nontransplanted wild-type mice2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar, 3Ramesh G. Reeves W.B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol: Renal Physiol. 2003; 54: F610-F618Crossref Scopus (219) Google Scholar, 14Ramesh G. Reeves W.B. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-a.Kidney Int. 2004; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar and suggests that the bone marrow transplant procedure itself does not affect the susceptibility to cisplatin-induced acute kidney injury. Of note, KO → WT mice developed similar degrees of renal failure as the WT → WT mice. In contrast, mice with a recipient TNF-α knockout background, whether they were transplanted with wild-type (WT → KO, BUN 60±11 mg/dl, and creatinine 0.33±0.05 mg/dl) or TNF-α knockout bone marrow (KO → KO, BUN 60±13 mg/dl, and creatinine 0.5±0.07 mg/dl) had substantially less renal failure than the mice with a wild-type background (P<0.01, n=6–12). The results in the KO → KO group confirm our earlier report that TNF-α knockout mice are resistant to cisplatin nephrotoxicity.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar GFR was also determined by fluorescein isothiocyanate (FITC)-inulin clearance as a more precise measure of renal function. As shown in Figure 3, mice with a wild-type background had severely reduced GFR 72 h after cisplatin treatment (WT → WT 18±4.5 μl/min, KO → WT 38±13 μl/min), whereas mice with a TNF-α knockout background, regardless of the genotype of their immune cells, had well-preserved renal function (KO → KO 196±7 μl/min, WT → KO 181±14 μl/min, P<0.01 vs WT → WT or KO → WT, n=3 in each group). The functional abnormalities in the chimeric mice were also reflected by structural changes in the kidney. Thus, 72 h after cisplatin treatment, kidneys with a wild-type background (WT → WT or KO → WT) showed severe tubular injury as evidenced by cast formation, loss of brush border membranes, sloughing of tubular epithelial cells, and dilation of tubules (Figure 4). These changes were minimal in kidneys from animals with a TNF-α knockout background (WT → KO, KO → KO). Semiquantitative assessment of histologic injury yielded tubular necrosis scores 3.1±0.2 in cisplatin-treated WT → WT mice, 2.8±0.2 in KO → WT mice, 1.5±0.4 in WT → KO mice, and 1.1±0.4 in KO → KO mice. The differences between wild-type background mice and TNF-α knockout background mice were significant (P<0.01, n=8–11). Leukocyte infiltration was measured using the napthol AS-D chloroacetate esterase stain. Thirty × 40 fields of esterase-stained sections were examined for quantitation of leukocytes. As shown in Figure 5, cisplatin injection produced a large increase in leukocytes within the kidney cortex in wild-type background chimeric mice (WT → WT 173±63, KO → WT 107±41). In contrast, TNF-knockout background mice (KO → KO 16±2, WT → KO 56±18) had significantly fewer infiltrating leukocytes (P<0.01, n=6–8). These results indicate that local production of TNF-α by resident renal cells is crucial to the recruitment of leukocytes to the kidney in cisplatin-induced nephrotoxicity. Cisplatin administration results in the upregulation of a number of proinflammatory cytokines and chemokines in the kidney. This upregulation was blunted in TNF-α knockout mice.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar Accordingly, we examined the expression of these cytokines in the TNF-α chimeric mice. Real-time reverse transcriptase-polymerase chain reaction (RT–PCR) was used to measure renal expression of certain inflammation-related genes (Figure 6). We previously demonstrated that Heme oxygenase 1, IL-1β, TNF-α, TNFR2, and MCP-1 are upregulated in the kidney after cisplatin injection.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar, 3Ramesh G. Reeves W.B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol: Renal Physiol. 2003; 54: F610-F618Crossref Scopus (219) Google Scholar, 14Ramesh G. Reeves W.B. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-a.Kidney Int. 2004; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar These responses were preserved in mice with a wild-type background (WT → WT and KO → WT) but were blunted in mice which lacked the ability to produce TNF-α in their kidneys (WT → KO and KO → KO). Cisplatin treatment increases serum TNF-α levels.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar, 3Ramesh G. Reeves W.B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol: Renal Physiol. 2003; 54: F610-F618Crossref Scopus (219) Google Scholar, 4Deng J. Kohda Y. Chiao H. et al.Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury.Kidney Int. 2001; 60: 2118-2128Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 5Tsuruya K. Ninomiya T. Tokumoto M. et al.Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death.Kidney Int. 2003; 63: 72-82Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 14Ramesh G. Reeves W.B. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-a.Kidney Int. 2004; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 15Zager R.A. Johnson A.C.M. Hanson S.Y. et al.Acute nephrotoxic and obstructive injury primes the kidney to endotoxin-driven cytokine/chemokine production.Kidney Int. 2006; 69: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 16Tsuruya K. Tokumoto M. Ninomiya T. et al.Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways.Am J Physiol Renal Physiol. 2003; 285: F208-F218Crossref PubMed Scopus (92) Google Scholar However, the source of the TNF-α is unknown. To address this issue, we measured the effect of cisplatin on serum TNF-α levels in the chimeric mice (Figure 7). Cisplatin injection increased serum TNF-α levels in WT → WT (158±28 pg/ml) and KO → WT (251±60 pg/ml) mice. However, TNF-α levels were lower in WT → KO (90±17 pg/ml, P<0.01, n=4–5) mice and, as expected, undetectable in KO → KO mice. These results indicate that a large portion of circulating TNF-α after cisplatin injection is derived from cells of nonimmune origin. We next measured cytokine and chemokine levels in the urine. As described in the Materials and Methods section, 16 cytokines were measured simultaneously in the urine using a multiplexed cytokine immunoassay. Upon cisplatin treatment, as shown in Figure 8, TNF-α, IP-10, IL-2, IL-6, and RANTES were detected in the urine. Of note, wild-type background mice secreted a large amount of TNF-α in urine. In contrast, there was no detectable TNF-α in the urine of mice deficient of TNF-α in their kidneys. These results suggest that resident renal cells are the major source of urinary TNF-α production. Likewise, mice with a recipient TNF-α knockout background had less urinary excretion of IL-2 and RANTES, suggesting that renal production of TNF-α is a stimulus for the renal production and excretion of these cytokines. In the murine model of cisplatin nephrotoxicity, cisplatin increases plasma and urine levels of TNF-α and increases renal expression of TNF-α mRNA. Moreover, TNF-α was shown to play a pathogenic role in cisplatin nephrotoxicity.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar However, the source of TNF-α which contributes to acute renal injury is not clear. In this regard, TNF-α is produced by a broad range of tissues and cells, including immune cells and intrinsic renal cells, such as mesangial cells,6Baud L. Oudinet J. Bens M. et al.Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide.Kidney Int. 1989; 35: 1111-1118Abstract Full Text PDF PubMed Scopus (185) Google Scholar,17Nakamura A. Johns E.J. Imaizumi A. et al.Role of angiotensin II-induced cAMP in mesangial TNF-alpha production.Cytokine. 2002; 19: 47-51Crossref PubMed Scopus (21) Google Scholar glomerular7Neale T. Ruger B. Macaulay H. et al.Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy.Am J Pathol. 1995; 146: 1444-1454PubMed Google Scholar,8Noiri E. Kuwata S. Nosaka K. et al.Tumor necrosis factor-alpha mRNA expression in lipopolysaccharide- stimulated rat kidney. Chronological analysis of localization.Am J Pathol. 1994; 144: 1159-1166PubMed Google Scholar and tubular epithelial cells,9Ramesh G. Reeves W.B. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice.Am J Physiol Renal Physiol. 2005; 289: F166-174Crossref PubMed Scopus (212) Google Scholar, 10Jevnikar A. Brennan D. Singer G. et al.Stimulated kidney tubular epithelial cells express membrane associated and secreted TNFa.Kidney Int. 1991; 40: 203-211Abstract Full Text PDF PubMed Scopus (143) Google Scholar, 11Wuthrich R.P. Glimcher L.H. Yui M.A. et al.MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells.Kidney Int. 1990; 37: 783-792Abstract Full Text PDF PubMed Scopus (233) Google Scholar and endothelial cells.12Albaugh G. Kann B. Strande L. et al.Nicotine induces endothelial TNF-alpha expression, which mediates growth retardation in vitro.J Surg Res. 2001; 99: 381-384Abstract Full Text PDF PubMed Scopus (29) Google Scholar,13Eissner G. Lindner H. Konur A. et al.Naive monocytes can trigger transendothelial migration of peripheral blood cells through the induction of endothelial tumour necrosis factor-alpha.Scand J Immunol. 2000; 51: 251-261Crossref PubMed Scopus (6) Google Scholar As cisplatin nephrotoxicity is associated with the influx of bone marrow-derived inflammatory cells into the kidney,2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar, 3Ramesh G. Reeves W.B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol: Renal Physiol. 2003; 54: F610-F618Crossref Scopus (219) Google Scholar, 9Ramesh G. Reeves W.B. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice.Am J Physiol Renal Physiol. 2005; 289: F166-174Crossref PubMed Scopus (212) Google Scholar, 14Ramesh G. Reeves W.B. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-a.Kidney Int. 2004; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar these infiltrating leukocytes could be the source of intrarenal and circulating TNF-α. On the other hand, we have shown that cisplatin stimulates renal epithelial cells to produce TNF-α in vitro9Ramesh G. Reeves W.B. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice.Am J Physiol Renal Physiol. 2005; 289: F166-174Crossref PubMed Scopus (212) Google Scholar,14Ramesh G. Reeves W.B. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-a.Kidney Int. 2004; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar raising the possibility that renal parenchymal cells are the major source of TNF-α in cisplatin nephrotoxicity. These studies were performed to determine the role of leukocyte-derived vs kidney-derived TNF-α in the pathogenesis of cisplatin nephrotoxicity. The approach used was to create chimeric mice in which the TNF-α gene was disrupted in cells of bone marrow origin or the kidney. This approach has been used to determine the importance of leukocyte TNFR2 expression in experimental hepatitis.18Schumann J. Muhlen K. Kiemer A. et al.Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice.J Immunol. 2003; 170: 2129-2137Crossref PubMed Scopus (18) Google Scholar An analogous approach has also been successfully employed to determine the site of TNF-α production in crescentic glomerulonephritis19Timoshanko J.R. Sedgwick J.D. Holdsworth S.R. et al.Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentric glomerulonephritis.J Am Soc Nephrol. 2003; 14: 1785-1793Crossref PubMed Scopus (90) Google Scholar and of adenosine agonist action20Day Y.-J. Huang L. McDuffie M.J. et al.Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells.J Clin Invest. 2003; 112: 883-891Crossref PubMed Scopus (206) Google Scholar and P-selectin production21Singbartl K.A.I. Forlow S.B. Ley K. Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure.FASEB J. 2001; 15: 2337-2344Crossref PubMed Scopus (129) Google Scholar in ischemic acute renal failure. The main finding of the current studies was that chimeric mice produced from wild-type recipients were equally susceptible to cisplatin nephrotoxicity regardless of whether their immune systems were from wild-type or TNF-α-deficient donors. In contrast, chimeras of TNF-α knockout recipients were resistant to nephrotoxicity regardless of the origin of their immune systems (Figures 1, 2 and 3). The lack of renal failure in the WT → KO mice can not be attributed to faulty production of TNF-α by the transplanted cells because we demonstrated that transplanted cells retain their ability to produce TNF-α (Figure 1) and circulating levels of TNF-α were detectable in the WT → KO mice (Figure 7). These results indicate that, despite the fact that cisplatin nephrotoxicity is characterized by the infiltration of inflammatory cells, TNF-α produced by bone marrow-derived cells does not contribute to cisplatin nephrotoxicity. Rather, production of TNF-α by renal parenchymal cells is probably responsible for the renal failure. We also noted that the influx of leukocytes into the kidney was reduced in WT → KO and KO → KO mice compared with KO → WT and WT → WT mice (Figure 5). This result indicates that the local production of TNF-α by resident kidney cells promotes an inflammatory response within the kidney. As both renal injury and leukocyte infiltration were reduced in mice with a TNFα-deficient background, our results do not establish if the reduction in the inflammatory infiltrate was the cause or the result of lessened kidney injury. Recent work from Rabb's group, however, demonstrated that early infiltration of the kidney by T cells is an important precedent to cisplatin injury.22Liu M. Chien C.C. Burne-Taney M. et al.Pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.J Am Soc Nephrol. 2006; 17: 765-774Crossref PubMed Scopus (134) Google Scholar In that study, deletion of T cells reduced cisplatin-induced renal dysfunction and also reduced kidney TNF-α content and infiltration of neutrophils and macrophages.22Liu M. Chien C.C. Burne-Taney M. et al.Pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.J Am Soc Nephrol. 2006; 17: 765-774Crossref PubMed Scopus (134) Google Scholar Our results indicate that the actions of T cells in cisplatin nephrotoxicity are not dependent upon the elaboration of TNF-α by those cells. Kidney expression of several chemokines and adhesion molecules is increased by cisplatin.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar In this regard, expression of MCP-1 was increased in WT → WT mice but not in WT → KO or KO → KO mice. Likewise, cisplatin increased the urinary excretion of RANTES in WT–WT mice but not in the other chimeras. The expression of intercellular adhesion molecule-1 (ICAM1) (not shown) was modestly increased in WT → WT, WT → KO, and KO → WT mice, but not in KO → KO mice. Thus, both renal and extrarenal production of TNF-α regulates the expression of different chemotactic factors and may account for the decreases in renal leukocyte infiltration seen in the WT → KO and KO → KO mice. Cisplatin increases both serum and urine concentrations of TNF-α.2Ramesh G. Reeves W.B. TNF-a mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (652) Google Scholar, 4Deng J. Kohda Y. Chiao H. et al.Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury.Kidney Int. 2001; 60: 2118-2128Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 22Liu M. Chien C.C. Burne-Taney M. et al.Pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.J Am Soc Nephrol. 2006; 17: 765-774Crossref PubMed Scopus (134) Google Scholar Cisplatin has been shown to increase TNF-α production by renal proximal tubule cells9Ramesh G. Reeves W.B. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice.Am J Physiol Renal Physiol. 2005; 289: F166-174Crossref PubMed Scopus (212) Google Scholar and by macrophages.23Singh R.K. Sodhi A. Singh S.M. Production of interleukin-1 and tumor necrosis factor by cisplatin-treated murine peritoneal macrophages.Natural Immunity & Cell Growth Regulation. 1991; 10: 105-116PubMed Google Scholar We found that serum levels of TNF-α were elevated to a similar extent in WT → WT and KO → WT mice but were significantly lower in WT
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