Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 micro, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5% compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39%; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of betaC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-gamma and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.
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PMID:Contribution of CD4+ T cells to the early mechanisms of ischemia- reperfusion injury in a mouse model of acute renal failure. 1740

Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan to N-formyl kynurenine and has a proapoptotic role in renal tubular epithelial cells (TEC) in response to IFN-gamma and TNF-alpha in vitro. TEC produce abundant amounts of IDO in vitro in response to inflammation but a pathological role for IDO in renal injury remains unknown. We investigated the role of IDO in a mouse model of renal ischemia-reperfusion injury (IRI). IRI was induced by clamping the renal pedicle of C57BL/6 mice for 45 min at 32 degrees C. Here, we demonstrate upregulation of IDO in renal tissue at 2 h after reperfusion which reached maximal levels at 24 h. Inhibition of IDO following IRI prevented the increase in serum creatinine observed in vehicle-treated mice (86.4 +/- 25 micromol/l, n = 11) compared with mice treated with 1-methyl-D-tryptophan, a specific inhibitor of IDO (33.7 +/- 8.7 micromol/l, n = 10, P = 0.031). The role of IDO in renal IRI was further supported by results in IDO-KO mice which maintained normal serum creatinine levels (32.5 +/- 2.0 micromol/l, n = 6) following IRI compared with wild-type mice (123 +/- 30 micromol/l, n = 9, P = 0.008). Our data suggest that attenuation of IDO expression within the kidney may represent a novel strategy to reduce renal injury as a result of ischemia reperfusion.
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PMID:Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury. 1848 Jan 71

Healthy liver, intestine, lung, and skin harbor resident lymphocytes with conventional and unconventional phenotypes. Lymphocytes also have been detected in healthy mice kidneys; however, these cells have not been well studied and have been largely overlooked. To better characterize the intra-renal lymphocytes, we extensively perfused C57BL/6J mice with PBS and then isolated mononuclear cells for flow cytometry analysis. We observed T cells, B cells, and NK cells in normal mice kidneys after extensive perfusion. Approximately 50% of kidney T lymphocytes expressed intermediate levels of CD3 (CD3int T cells). Similar to liver and lung, a high percentage of unconventional CD3+CD4(-)CD8(-) double-negative T cells was observed in normal mice kidneys, from which 11% expressed B220 antigen. Unlike the spleen and blood, the classic CD4+ and CD8+ T lymphocytes in the kidney had a high proportion of activated CD69+ and effector/memory CD44- CD62L ligand phenotypes. Also, a small percentage of CD4+CD25+forkhead box p3+ and NKT cells was observed in perfused and exanguinated kidneys. In addition, a distinct TCR repertoire was found on intra-renal conventional and unconventional T cells compared with those from the spleen. Finally, after 24 h of renal ischemia reperfusion injury (IRI), increased production of cytokines IFN-gamma and TNF-alpha by CD4+ and CD8+ T cells, isolated from perfused kidneys, was observed. These data suggest that some of these cells harbored in the kidney could be implicated in the immune response of the IRI pathogenic process.
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PMID:Normal mouse kidneys contain activated and CD3+CD4- CD8- double-negative T lymphocytes with a distinct TCR repertoire. 1876 77

This study investigated whether the renal regeneration occurring in the recovery phase of kidney ischemia-reperfusion (I/R) is mediated by endogenously generated lipocalin-2 (Lcn2). A second objective was to examine whether Lcn2-mediated cell effects could be regulated by the inflammatory cytokines in the environment through their action on Lcn2 receptors (Lcn2R and megalin). Male Swiss mice were subjected to 30 min of renal ischemia with a reperfusion period of 24 h (early reperfusion, expected time for maximum inflammation) and 96 h (late reperfusion, expected time for maximum regeneration). Different experimental groups underwent I/R, I/R with iv anti-mouse Lcn2 monoclonal antibody injected during the early/inflammatory or late/recovery phase, and I/R with proinflammatory cytokine cocktail administration (recombinant mouse IL-1beta, TNF-alpha, and IFN-gamma). Compared with control nonischemic mice, the expression of three proliferation markers (stathmin, PCNA, and Ki-67, analyzed by quantitative RT-PCR) increased significantly in the I/R-treated animals. Blockade of Lcn2 by addition of anti-Lcn2 antibody significantly decreased the expression of these three proliferation markers when administered in the late/reparative phase, but had the opposite effect when administered in the early/inflammatory phase. Proinflammatory cytokine cocktail administration reduced the proliferative effects of Lcn2, and repressed Lcn2R and megalin expression. In conclusion, endogenously generated Lcn2 induces renal cell regeneration depending on the inflammatory cytokines in kidney I/R.
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PMID:Lipocalin-2-induced renal regeneration depends on cytokines. 1881 20

Renal ischemia-reperfusion injury (IRI) can result in acute renal failure with mortality rates of 50% in severe cases. NK cells are important participants in early-stage innate immune responses. However, their role in renal tubular epithelial cell (TEC) injury in IRI is currently unknown. Our data indicate that NK cells can kill syngeneic TEC in vitro. Apoptotic death of TEC in vitro is associated with TEC expression of the NK cell ligand Rae-1, as well as NKG2D on NK cells. In vivo following IRI, there was increased expression of Rae-1 on TEC. FACS analyses of kidney cell preparations indicated a quantitative increase in NKG2D-bearing NK cells within the kidney following IRI. NK cell depletion in wild-type C57BL/6 mice was protective, while adoptive transfer of NK cells worsened injury in NK, T, and B cell-null Rag2(-/-)gamma(c)(-/-) mice with IRI. NK cell-mediated kidney injury was perforin (PFN)-dependent as PFN(-/-) NK cells had minimal capacity to kill TEC in vitro compared with NK cells from wild-type, FasL-deficient (gld), or IFN-gamma(-/-) mice. Taken together, these results demonstrate for the first time that NK cells can directly kill TEC and that NK cells contribute substantially to kidney IRI. NK cell killing may represent an important underrecognized mechanism of kidney injury in diverse forms of inflammation, including transplantation.
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PMID:NK cells induce apoptosis in tubular epithelial cells and contribute to renal ischemia-reperfusion injury. 1901 38

It is well-established that significant ischemia-reperfusion injury during kidney transplantation results in increased incidence of long-term fibrosis and rejection. To test for a role of T cell infiltration and activation following ischemic injury, we induced both bilateral and unilateral renal ischemia in mice, followed by reperfusion, and then isolated mononuclear cells. Analysis of these cells by flow cytometry showed that 2 weeks after bilateral ischemia there was a significant increase of CD8(+) T cells. Furthermore, both CD4(+) and CD8(+) T cells infiltrated the injured kidney 6 weeks after unilateral ischemia. These T cells had increased expression of CD69(+) and CD44(hi)CD62L(-), markers of activation and effector-memory, respectively. CD4(+)NK1.1(+) and CD19(+) B cells were decreased in percentage both 6 and 11 weeks after bilateral or unilateral injury. There was a significant upregulation of IL-1beta, IL-6, TNF-alpha, IFN-gamma, MIP-2, and RANTES expression, measured by real-time PCR, 6 weeks after unilateral renal ischemia, further indicating T cell activation. Depletion of CD4(+) and CD8(+) T cells before ischemia caused less medullary damage and reduced kidney IFN-gamma expression, whereas their depletion following ischemia increased kidney IL-1beta; however, depletion of these cells had no effect on histological damage to the kidney. Our study demonstrates that moderate or severe kidney ischemia induces long-term T lymphocyte infiltration and cytokine/chemokine upregulation, leading to kidney structural changes.
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PMID:Renal ischemia-reperfusion leads to long term infiltration of activated and effector-memory T lymphocytes. 1909 96

Renal ischemia and reperfusion injury (IRI) is considered an inflammatory syndrome. To move forward in its pathogenesis, we exploited the role of several cytokines on renal damages triggered by IRI. Specifically to evaluate the role of Th1 immune profile in this system, IL-12, IFN-gamma, and IFN-gamma/IL-12 deficient (KO) mice on C57BL/6 background and their controls were subjected to IRI. In each group, blood and kidney samples were harvested. Renal function was evaluated by serum creatinine and renal morphometric analyses. Gene expression of IL-6 and HO-1 were also investigated by Q-PCR. IFN-gamma KO animals presented the highest impairment in renal function compared to controls. Conversely, IL-12 KO animals were absolutely protected and, in a lesser extent, IFN-gamma/IL-12 KO double knockout was also protected from IRI. Gene expression analyses showed higher expression of HO-1, a cytoprotective gene, and IL-6, a pro-inflammatory cytokine, in IFN-gamma deficient animals subjected to IRI. Our results confirm that Th1 related cytokines such as IL-12 and IFN-gamma are critically involved in renal ischemia and reperfusion injury.
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PMID:Critical involvement of Th1-related cytokines in renal injuries induced by ischemia and reperfusion. 1909 86

During renal ischemia-reperfusion, local and distant tissue injury is caused by an influx of neutrophils into the affected tissues. Here we measured the kinetics of margination and transmigration of neutrophils in vivo in the kidney and lungs following renal ischemia-reperfusion. After bilateral renal injury, kidney neutrophil content increased threefold at 24 h. The neutrophils were found primarily in the interstitium and to a lesser degree marginated to the vascular endothelium. These interstitial neutrophils had significantly lower levels of intracellular IFN-gamma, IL-4, IL-6, and IL-10 a tendency for decreased amounts of IL-4 and TNF-alpha compared to the marginated neutrophils. Localization of the neutrophils to the kidney interstitium was confirmed by high resolution microscopy and these sites of transmigration were directly associated with areas of increased vascular permeability. Activation of the adenosine 2A receptor significantly decreased both kidney neutrophil transmigration by about half and vascular permeability by about a third. After unilateral renal ischemia-reperfusion, the unclipped kidney and lungs did not accumulate interstitial neutrophils or have increased vascular permeability despite a marked increase of neutrophil margination in the lungs. Our findings suggest there is a sequential recruitment and transmigration of neutrophils from the vasculature into the kidney interstitium at the site of tissue injury following renal ischemia-reperfusion.
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PMID:Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. 1928 58

Although previous studies have demonstrated that microvascular dysfunction and inflammation occur in ischemia-reperfusion injury (IRI), the underlying mechanisms are poorly understood. We hypothesized that T cells could mediate renal vascular permeability (RVP) during IRI. We evaluated renal vascular permeability by extravasation of Evans blue dye from the kidney in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice in our mouse model of kidney ischemia-reperfusion injury. In wild type mice, RVP was significantly increased at 3 h, peaked at 6 h and declined by 24 h after ischemia. Immunohistochemistry revealed that CD3(+) T cells trafficked into ischemic kidney at 1 h and peaked at 6 h. Gene microarray analysis demonstrated that endothelial-related genes including TNF-alpha were up-regulated in ischemic kidney. The production of TNF-alpha and IFN-gamma protein was increased in CD3 and CD4 T cells from the blood and kidney after ischemia. The rise in RVP after ischemia in wild type mice was attenuated in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice. The attenuation of RVP in CD3 T-cell deficient mice after ischemia was restored by adoptive transfer of T cells from WT mice. Our data demonstrate that T cells directly contribute to the increased RVP after kidney ischemia-reperfusion, potentially through T cell cytokine production.
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PMID:Effect of T cells on vascular permeability in early ischemic acute kidney injury in mice. 1932 71

The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-gamma signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-gamma pathway and NKT cells by administering alpha-galactosylceramide-primed bone marrow-derived DCs increased IFN-gamma production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-gamma production in either Il17a-/- or Il17r-/- mice, which suggested that IL-17 signaling was proximal to IFN-gamma signaling. This was confirmed by the finding that IFN-gamma administration reversed the protection seen in Il17a-/- mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng-/- mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-gamma and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-gamma. These mechanisms might contribute to reperfusion injury in other organs.
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PMID:IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. 2003 94


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