Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The object of the study presented here was to test whether measurement of blood or urine IL-6 or TNF-alpha could discriminate between the most common causes of renal allograft dysfunction, thus avoiding a biopsy. We present data here in which serum and urine IL-6 and TNF-alpha levels were measured at the same time as a diagnostic renal biopsy was performed. TNF-alpha and IL-6 were measured by sandwich ELISA. Thirty patients had acute cellular rejection, 18 had acute tubular necrosis/CsA toxicity, and 9 had chronic vascular rejection. There was no difference in the levels of IL-6 measured in serum and urine among the three categories of graft dysfunction (t < 1.31; P > 0.20). A similar result with considerable overlap between the groups was seen with TNF-alpha (t < 0.78; P > 0.44). Stratifying the results according to the precise immunosuppressive therapy, CsA dose, body weight, CsA level, body temperature, serum creatinine, the number of previous rejection episodes, original cause of renal failure, or the time elapsed since the transplant did not alter the results. The ratio of serum IL-6 divided by trough CsA level was compared among the three groups and there was no significant difference among them (t < 1.79; P > 0.09). In the light of our results, we therefore suggest that previously published reports of the clinical value of serum and or urine IL-6 and or TNF-alpha in relatively small numbers of patients, not all of whom had been biopsied and in whom rigorous clinical and statistical criteria had not been met, should be viewed with caution.
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PMID:Serum and urine IL-6 and TNF-alpha in renal transplant recipients with graft dysfunction. 821 2

The systemic symptoms, tissue lesions and release of cytokines were analysed in four isogenic mouse strains with distinct haplotypes injected with various doses of Loxosceles intermedia spider venom. The estimated LD50 were 24.5 microg for C57Bl/6, 17.6 microg for BALB/c, 6.3 microg for C3H/HeJ and 4.6 microg for A/Sn mice. Prostration, acute cachexia, hypothermia, neurological disorders and hemoglobinuria were the signals preceding death. Accumulation of eosinophilic material inside the proximal and distal renal tubules and acute tubular necrosis were the most common histopathological findings. Death was prevented by previous treatment of venom with specific antivenom serum. The protein F35 purified from the whole venom retained the ability to induce the symptoms of the whole venom. The cytokines tumor necrosis factor (TNF), interleukins IL-6 and IL-10 and the radical nitric oxide were detected in serum at different levels after venom injection. These findings indicate that the state of shock produced in mice by whole endotoxin-free L. intermedia venom or by its purified fraction, protein F35, mimics the endotoxemic shock, that susceptibility to the systemic effects of the venom varies among mice of different haplotypes and that the pattern of in vivo cytokine release resembles that of endotoxemic shock.
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PMID:Endotoxemic-like shock induced by Loxosceles spider venoms: pathological changes and putative cytokine mediators. 962 May 87

C-reactive protein (CRP) is the main acute phase reactant in humans. Its production is presumably restricted to the liver but extrahepatic expression by inflamed tissue has not been studied in detail. By real-time PCR and immunohistochemistry we here show that renal cortical tubular epithelial cells (TEC) express CRP mRNA and protein within 6 h after stimulation with conditioned medium (CM) or IL-6, but not IL-1alpha or TNF-alpha. Western blot analysis with monoclonal anti-CRP antibody that recognizes native CRP revealed protein secretion into supernatants of CM-stimulated TEC cultures. While hepatoma-derived Hep3B cells could be induced similarly, peripheral blood mononuclear cells could not. CRP mRNA transcripts were observed in nephrectomized renal allografts with severe acute rejection but not with chronic allograft nephropathy (CAN). Of 19 needle biopsies of acutely rejecting kidney transplants, 15 demonstrated CRP mRNA production with the relative expression levels increasing with the severity of rejection. On the other hand, none of 7 graft biopsies with acute tubular necrosis (ATN) or CAN showed CRP mRNA expression. By using monoclonal anti-CRP antibody, cortical tubules as well as glomerular cells were shown to locally express CRP in rejecting, but not in ATN kidneys. We conclude that inflamed kidneys represent a so far unknown site of CRP formation in vivo. These data shed new light on the acute phase reaction not merely representing a systemic inflammatory pathway but probably being part of the local immune response.
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PMID:The kidney as a second site of human C-reactive protein formation in vivo. 1259 44

Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against oxidative stress. We hypothesized that CO would protect ischemia-reperfusion (I/R) injury of transplanted organs, and the efficacy of CO was studied in the rat kidney transplantation model. A Lewis rat kidney graft, preserved in University of Wisconsin solution at 4 degrees C for 24 h, was orthotopically transplanted into syngeneic rats. Recipients were maintained in room air or exposed to CO (250 ppm) in air for 1 h before and 24 h after transplantation. Animals were killed 1, 3, 6, and 24 h after transplantation to assess efficacy of inhaled CO. Rapid upregulation of mRNA for IL-6, IL-1beta, TNF-alpha, ICAM-1, heme oxygenase-1, and inducible nitric oxide synthase was observed within 3 h after transplantation in the control grafts of air-exposed recipients, associating with histopathological evidences of acute tubular necrosis, interstitial hemorrhage, and edema. In contrast, the increase of inflammatory mediators was markedly inhibited in kidney grafts of CO-treated recipients, which correlated with improved renal cortical blood flow. Further detailed morphological analyses revealed that CO preserved the glomerular vascular architecture and podocyte viability with less apoptosis of tubular epithelial cells and less ED1(+) macrophage infiltration. CO inhalation resulted in improved serum creatinine levels and clearance, and animal survival was significantly improved with CO to 60.5 from 25 days in untreated controls. The study demonstrates that exposure of kidney graft recipients to CO at a low concentration can impart significant protective effects against renal I/R injury and improve function of renal grafts.
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PMID:Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. 1529 46

The aim of our study was to correlate intragraft mRNA expression of cytokines and growth factors with histopathologic features in renal allograft biopsies. Fifty-six core biopsies performed in 51 kidney transplant recipients were assessed by the Banff '97 classification. Tubular and glomerular expressions of IFN-gamma, TGF-beta1, and PDGF-B as well as IL-2, IL-6, and IL-10 mRNA were assessed using semiquantitative RT-PCR in situ. No significant differences were noted between acute cellular and vascular rejection with regard to the glomerular and tubular mRNA expression of cytokines examined. We observed a positive correlation between tubular and glomerular IL-10 and IFN-gamma mRNAs during acute rejection. In chronic rejection the mRNA expression levels of IFN-gamma and IL-2, IL-6, and IL-10 did not differ from those of acute rejection; moreover, the glomerular expression of mRNA for TGF-beta1 (P < .05) and PDGF-B (P < .1) was even lower than during acute rejection episodes. Both tubular and glomerular IL-2, TGF-beta1, and PDGF-B mRNA expression levels in biopsies with acute rejection were significantly higher than in acute tubular necrosis (ATN). Biopsy samples with borderline changes exhibited the lowest levels of cytokine gene expression and were close to the intensity of control specimens obtained from living donor kidney biopsies taken during organ harvest. Our data failed to show a dichotomy between Th1 and Th2 cytokine activation in biopsy specimens from kidney allograft recipients; both Th1- and Th2-derived cytokines were involved to similar extents in rejection processes.
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PMID:Intragraft mRNA expression of cytokines and growth factors in human kidney allograft biopsies by in situ RT-PCR analysis. 1584 25

Ischemic-reperfusion injury (IRI) triggers an inflammatory response involving neutrophils/macrophages, lymphocytes and endothelial cells. Galectin-3 is a multi-functional lectin with a broad range of action such as promotion of neutrophil adhesion, induction of oxidative stress, mastocyte migration and degranulation, and production of pro-inflammatory cytokines. The aim of this study was evaluate the role of galectin-3 in the inflammation triggered by IRI. Galectin-3 knockout (KO) and wild type (wt) mice were subjected to 45 min of renal pedicle occlusion. Blood and kidney samples were collected at 6, 24, 48 and 120 h. Blood urea was analyzed enzymatically, while MCP-1, IL-6 and IL-1beta were studied by real-time PCR. Reactive oxygen species (ROS) was investigated by flow cytometry. Morphometric analyses were performed at 6, 24, 48 and 120 h after reperfusion. Urea peaked at 24 h, being significantly lower in knockout animals (wt = 264.4 +/- 85.21 mg/dl vs. gal-3 KO = 123.74 +/- 29.64 mg/dl, P = 0.001). Galectin-3 knockout animals presented less acute tubular necrosis and a more prominent tubular regeneration when compared with controls concurrently with lower expression of MCP-1, IL-6, IL-1beta, less macrophage infiltration and lower ROS production at early time points. Galectin-3 seems to play a role in renal IRI involving the secretion of macrophage-related chemokine, pro-inflammatory cytokines and ROS production.
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PMID:A Role for galectin-3 in renal tissue damage triggered by ischemia and reperfusion injury. 1865 91

IL-18 function is neutralized in IL-18 binding protein transgenic (IL-18BP Tg) mice. First, we determined whether IL-18BP Tg mice are protected against ischemic acute kidney injury (AKI). Ischemic AKI was induced by bilateral renal pedicle clamping. IL-18BP Tg mice were functionally and histologically protected against ischemic AKI as determined by blood urea nitrogen, serum creatinine, and acute tubular necrosis score. We have demonstrated that the injurious effect of IL-18 in the kidney is independent of neutrophils and lymphocytes. Thus the effect of IL-18 inhibition on renal macrophage infiltration was determined. The number of macrophages was significantly reduced in IL-18BP Tg compared with wild-type kidneys. To determine the cytokines and chemokines that are dependent on IL-18, we performed flow cytometry based assays. Multiple chemokines/cytokines, IL-3, IL-6, IL-15, IL-18, leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 were significantly increased in AKI vs. sham kidneys. Only CXCL1 (also known as KC or IL-8) was significantly increased in AKI vs. sham kidneys and significantly reduced in IL-18BP Tg AKI vs. wild-type AKI kidneys. To determine whether macrophages are the source of CXCL1 in the kidney, we depleted macrophages with liposomal encapsulated clodronate. CXCL1 was significantly decreased in macrophage-depleted vs. control AKI mice. In summary, in ischemic AKI in mice, 1) IL-18BP Tg mice are functionally and histologically protected, 2) macrophage infiltration in the kidney and CXCL1 are significantly reduced in IL-18BP Tg mice, and 3) macrophage depletion significantly reduces CXCL1 in the kidney. In conclusion, protection against ischemic AKI in IL-18BP Tg mice is associated with less macrophage infiltration and less production of CXCL1 in the kidney.
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PMID:Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury. 1875 96

Ischemia and reperfusion injury (IR) is an antigen independent inflammatory process that causes tissue damage. After IR, kidneys up-regulate leukocyte adhesion molecules and toll-like receptors (TLRs). Moreover, injured kidneys can also secrete factors (i.e. heat shock protein) which bind to TLRs and trigger intracellular events culminating with the increase in the gene expression of inflammatory cytokines. FTY720 is an immunomodulatory compound and protects at least in part kidneys submitted to IR. The mechanisms associated with FTY720's beneficial effects on kidneys after IR remain elusive. We investigated whether FTY720 administration in mice submitted to kidney IR is associated with modulation of TLR2 and TLR4 expression. C57BL/6 mice submitted to 30min of renal pedicles clamp were evaluated for serum parameters (creatinine, urea and nitric oxide), kidney histology, spleen and kidney infiltrating cells expression of TLR2 and TLR4, resident kidney cells expression of TLR2 and TLR4 and IL-6 protein expression in kidney. FTY720-treated mice presented decrease in serum creatinine, urea and nitric oxide, diminished expression of TLR2 and TLR4 both in spleen and kidney infiltrating cells, and reduced kidney IL-6 protein expression in comparison with IR non-treated mice. However, acute tubular necrosis was present both in IR non-treated and IR+FTY720-treated groups. Also, FTY720 did not prevent TLR2 and TLR4 expression in kidney resident cells. In conclusion, FTY720 can promote kidney function recovery after IR by reducing the inflammatory process. Further studies are needed in order to establish whether TLR2 and TLR4 down regulation should be therapeutically addressed as protective targets of renal function and structure after IR.
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PMID:TLR2 and TLR4 expression after kidney ischemia and reperfusion injury in mice treated with FTY720. 2157 Nov

The ischemia-reperfusion injury (IRI) remains a major problem in transplantation. The objective of this study was to evaluate the effects of preconditioning a donor group with rapamycin and another donor group with tacrolimus to prevent IRI. Twelve hours before nephrectomy, donor Wistar rats received immunosuppressive drugs. The sample was divided into four experimental groups: a sham group, an untreated control group, a group treated with rapamycin (2 mg/kg) and a group treated with tacrolimus (0.3 mg/kg). Left kidneys were removed and, after three hours of cold ischemia, grafts were transplanted. Twenty-four hours later, the transplanted organs were recovered for histological analysis and evaluation of cytokine expression. The pre-conditioning treatment with rapamycin or tacrolimus significantly reduced donor blood urea nitrogen and creatinine levels compared with control group (BUN: p < 0.001 vs. control and creatinine: p < 0.001 vs. control). Acute tubular necrosis was significantly lower in donors treated with immunosuppressant drugs compared with the control group (p < 0.001). Finally, inflammatory cytokines such as TNF-a, IL-6 and rIL-21 showed lower levels in the graft of pre-treated animals. This exploratory experimental study shows that preconditioning donors with rapamycin and tacrolimus in different groups improves clinical outcome and pathology in recipients and reduces in situ pro-inflammatory cytokines associated with Th17 differentiation, creating a favorable environment for the differentiation of regulatory T cells (Tregs).
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PMID:[Immunosuppression in kidney donors with rapamycin and tacrolimus. Proinflammatory cytokine expression]. 2225 48

Age increases the risk for ischemic acute kidney injury (AKI). We questioned whether a similar age-dependent injury occurs following exposure to hemoglobin, a known nephrotoxin. Old mice (~16 mo old), but not young mice (~6 mo old), when administered hemoglobin, exhibited marked elevation in blood urea nitrogen (BUN) and serum creatinine, and acute tubular necrosis with prominent tubular cast formation. The aged kidney exhibited induction of heme oxygenase-1 (HO-1) and other genes/proteins that may protect against heme-mediated renal injury, including ferritin, ferroportin, haptoglobin, and hemopexin. Old mice did not evince induction of HO-2 mRNA by hemoglobin, whereas a modest induction of HO-2 mRNA was observed in young mice. To determine the functional significance of HO-2 in heme protein-induced AKI, we administered hemoglobin to relatively young HO-2(+/+) and HO-2(-/-) mice: HO-2(-/-) mice, compared with HO-2(+/+) mice, exhibited greater renal dysfunction and histologic injury when administered hemoglobin. In addition to failing to elicit a protective system such as HO-2 in response to hemoglobin, old mice exhibited an exaggerated maladaptive response typified by markedly greater induction of the nephrotoxic cytokine IL-6 (130-fold increase vs. 10-fold increase in mRNA in young mice). We conclude that aged mice, unlike relatively younger mice, are exquisitely sensitive to the nephrotoxicity of hemoglobin, an effect attended by a failure to induce HO-2 mRNA and a fulminant upregulation of IL-6. Age thus markedly augments the sensitivity of the kidney to heme proteins, and HO-2 confers resistance to such insults.
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PMID:Age sensitizes the kidney to heme protein-induced acute kidney injury. 2336 2


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