Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In animals models, exposure of the brain, heart, or kidneys to sublethal ischemia induces tolerance for subsequent ischemia. However, the ability of human renal cells to undergo hypoxic preconditioning has not been evaluated. In addition, it is unclear if renal ischemic preconditioning induces resistance at the cellular level, or if preconditioning is a result of altered postischemic hemodynamics or the azotemic environment. In this study, we tested the ability of cultured human proximal tubular epithelial cells (PTEC) to undergo hypoxic preconditioning at the cellular level. Hypoxia was induced by incubating cells in an anaerobic incubator in glucose-free buffer (combined oxygen-glucose deprivation; COGD). Cell injury was assessed by lactate dehydrogenase (LDH) efflux, release of arachidonic acid metabolites, and light microscopy. PTEC preconditioned with 12 h of COGD and a 24-h recovery period had less LDH efflux than control PTEC after subsequent exposure to 20 h of COGD (15.0 +/- 2.5% vs. 44.0 +/- 3.4%, p < 0.05). Preconditioned PTEC also retained relatively normal morphology and had less release of arachidonic acid metabolites than control PTEC. Because renal ischemia is characterized predominately by tubular injury with relative sparing of the glomerulus, we determined if PTEC are more susceptible to hypoxic injury than glomerular cells. For further comparison, we also assessed the susceptibility to hypoxia of the porcine tubular epithelial cell line LLC-PK1. After exposure to 18 h of COGD, LDH efflux from PTEC (25.5 +/- 3.3%, mean +/- SEM) was lower than from LLC-PK1 cells (47.6 +/- 4.0%; p < 0.01), but not mesangial cells (22.7 +/- 5.0%) or glomerular endothelial cells (38.2 +/- 6.2%). In conclusion, we have demonstrated that cultured PTEC are as resistant to hypoxic injury as glomerular cells, and that PTEC attain cytoresistance after hypoxic preconditioning. Characterization of the molecular changes that occur in human PTEC after hypoxic preconditioning may reveal innate survival mechanisms that can be manipulated to promote protection from renal ischemia in patients.
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PMID:Susceptibility of human proximal tubular cells to hypoxia: effect of hypoxic preconditioning and comparison to glomerular cells. 904 51

Heat shock produces cellular tolerance to a variety of adverse conditions; however, the protective effect of heat shock on renal cell ischemic injury remains unclear. Protein kinase C (PKC) has been implicated in the signaling mechanisms of acute preconditioning, yet it remains unknown whether PKC mediates heat shock-induced delayed preconditioning in renal cells. To study this, renal tubular cells (LLC-PK1) were exposed to thermal stress (43 degrees C) for 1 h and heat shock protein (HSP) 72 induction was confirmed by Western blot analysis. Cells were subjected to simulated ischemia 24 h after thermal stress, and the effect of heat shock (delayed preconditioning) on ischemia-induced apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) and B cell lymphoma 2 (Bcl(2)) expression (Western) was determined. Subsequently, the effect of PKC inhibition on HSP72 induction and heat stress-induced ischemic tolerance was evaluated. Thermal stress induced HSP72 production, increased Bcl(2) expression, and prevented simulated ischemia-induced renal tubular cell apoptosis. PKC inhibition abolished thermal induction of HSP72 and prevented heat stress-induced ischemic tolerance. These data demonstrate that thermal stress protects renal tubular cells from simulated ischemia-induced apoptosis through a PKC-dependent mechanism.
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PMID:Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism. 1140 13

Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43 degrees Cx1 hour) in renal tubular cells (LLC-PK1) with Western blot confirmation. Cells were subjected to simulated ischemia 24 hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72 on nuclear factor-kappaB (NF-kappaB) activation (electrophoretic mobility shift assay and immunohistochemistry), IkappaBalpha production (Western blot), postischemic tumor necrosis factor-alpha (TNF-alpha) production (RT-PCR), and apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF-alpha in apoptosis was determined (anti-TNF-alpha neutralizing antibody). Results demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72 prevented NF-kappaB activation and translocation, TNF-alpha gene transcription, and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF-alpha neutralization also inhibited ischemia-induced renal tubular cell apoptosis. These results indicate that liposomal delivery of HSP72 inhibits ischemia-induced renal tubular cell apoptosis by preventing NF-kappaB activation and subsequent TNF-alpha production. Further elucidation of the mechanisms of HSP-induced cytoprotection may result in therapeutic strategies that limit or prevent ischemia-induced renal damage.
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PMID:Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis. 1259 41

The Wnt-beta-catenin pathway plays key roles in embryogenesis. Wnt-4 is known to be expressed in the mesonephric duct in embryonic development. It is tempting to speculate that the Wnt-4-beta-catenin pathway contributes to the recovery from acute renal failure (ARF). This study used an in vivo model of ARF rats to clarify the significance of the Wnt-4-beta-catenin pathway in ARF. ARF was induced by clamping the rat left renal artery for 1 h. At 3, 6, 12, 24, 48, and 72 h after reperfusion, whole kidney homogenate and total RNA were extracted for examination by Western blot analysis and real-time RT-PCR. Wnt-4 mRNA and protein expression were strongly increased at 3 to 12 h and 6 to 24 h after ischemia, respectively. In immunohistologic examination, Wnt-4 was expressed in the proximal tubules and co-expressed with aquaporin-1, GM130, and PCNA. Cyclin D1 and cyclin A were expressed at 24 to 48 h after reperfusion. In addition, the overexpression of Wnt-4 and beta-catenin promoted the cell cycle and increased the promoter activity and protein expression of cyclin D1 in LLC-PK1 cells. Taken together, these data suggest that the Wnt-4-beta-catenin pathway plays a key role in the cell cycle progression of renal tubules in ARF. The Wnt-4-beta-catenin pathway may regulate the transcription of cyclin D1 and control the regeneration of renal tubules in ARF.
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PMID:Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats. 1270 92

We have previously shown that microtubule-organizing centers (MTOCs) attach to the apical network of intermediate filaments (IFs) in epithelial cells in culture and in epithelia in vivo. Because that attachment is important for the architecture of microtubules (MTs) in epithelia, we analyzed whether chemical anoxia in LLC-PK1 and CACO-2 cells or unilateral ischemia-reperfusion in rat kidney (performed under fluorane anesthesia) had an effect on the binding and distribution of MTOCs. In culture, we found that chemical anoxia induces MTOC detachment from IFs by morphological and biochemical criteria. In reperfused rat proximal tubules, noncentrosomal MTOCs were fully detached from the cytoskeleton and scattered throughout the cytoplasm at 3 days after reperfusion, when brush borders were mostly reassembled. At that time, MTs were also fully reassembled but, as expected, lacked their normal apicobasal orientation. Two apical membrane markers expressed in S2 and S3 segments were depolarized at the same stage. At 8 days after reperfusion, membrane polarity, MTOCs, and MTs were back to normal. Na+-K+-ATPase was also found redistributed, not to the apical domain but rather to an intracellular compartment, as described by others (Alejandro VS, Nelson W, Huie P, Sibley RK, Dafoe D, Kuo P, Scandling JD Jr., and Myers BD. Kidney Int 48: 1308-1315, 1995). The prolonged depolarization of the apical membrane may have implications in the pathophysiology of acute renal failure.
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PMID:Membrane repolarization is delayed in proximal tubules after ischemia-reperfusion: possible role of microtubule-organizing centers. 1270 92

The protective effect of (-)-epicatechin 3-O-galate (ECg) against peroxynitrite (ONOO-)-mediated damage was examined using an animal model and a cell culture system. In rats subjected to lipopolysaccharide (LPS) administration plus ischemia-reperfusion, the plasma 3-nitrotyrosine level an indicator of ONOO- production in vivo, was elevated, whereas it declined significantly and dose-dependently after the oral administration of ECg at doses of 10 and 20 micromoles/kg body weight/day for 20 days prior to the process. Moreover, oral administration of ECg significantly enhanced the activities of the antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase, and the antioxidant glutathione, showing enhancement of the biological defense system against the damage induced by ONOO-. In addition, the significant increase in the renal mitochondrial thiobarbituric acid-reactive substance level of LPS and ischemic-reperfused control rats was attenuated in rats given ECg. Furthermore, the elevations in the plasma urea nitrogen and creatinine (Cr) levels and the urinary methylguanidine/Cr ratio induced by the procedure were attenuated markedly after oral administration of ECg, implying amelioration of renal impairment. The addition of ECg (25 or 125 microM) prior to 3-morpholinosydnonimine (SIN-1, 800 microM) exposure reduced ONOO- formation and increased the viability of cultured renal epithelial (LLC-PK1) cells in a dose-dependent manner. In particular, ECg inhibited ONOO(-)-mediated apoptotic cell death, which was confirmed by decreases in the DNA fragmentation rate and the presence of apoptotic morphological changes, i.e. small nuclei and nuclear fragmentation. Furthermore, adding ECg before SIN-1 treatment regulated the cell cycle by enhancing G2/M phase arrest. This study provides evidence that ECg has protective activity against the renal damage induced by excessive ONOO- in cellular and in vivo systems.
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PMID:Protective activity of (-)-epicatechin 3-O-gallate against peroxynitrite-mediated renal damage. 1279 78

We evaluated the effects of SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure. Ischemic acute renal failure in rats was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the contralateral nephrectomy. SEA0400 administration (0.3, 1 and 3 mg/kg, i.v.) before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction and histological damage such as tubular necrosis. SEA0400 pretreatment at the higher dose suppressed the increment of renal endothelin-1 content after reperfusion. The ischemia/reperfusion-induced renal dysfunction was also overcome by post-ischemia treatment with SEA0400 at 3 mg/kg, i.v. In in vitro study, SEA0400 (0.2 and 1 microM) protected cultured porcine tubular cells (LLC-PK1) from hypoxia/reoxygenation-induced cell injury. These findings support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury. The possibility exists that a selective Na+/Ca2+ exchange inhibitor such as SEA0400 is useful as effective therapeutic agent against ischemic acute renal failure in humans.
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PMID:A novel and selective Na+/Ca2+ exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury. 1457 4

Cellular ATP depletion in diverse cell types results in the net conversion of monomeric G-actin to polymeric F-actin and is an important aspect of cellular injury in tissue ischemia. We propose that this conversion results from altering the ratio of ATP-G-actin and ADP-G-actin, causing a net decrease in the concentration of thymosinactin complexes as a consequence of the differential affinity of thymosin beta4 for ATP- and ADP-G-actin. To test this hypothesis we examined the effect of ATP depletion induced by antimycin A and substrate depletion on actin polymerization, the nucleotide state of the monomer pool, and the association of actin monomers with thymosin and profilin in the kidney epithelial cell line LLC-PK1. ATP depletion for 30 min increased F-actin content to 145% of the levels under physiological conditions, accompanied by a corresponding decrease in G-actin content. Cytochalasin D treatment did not reduce F-actin formation during ATP depletion, indicating that it was predominantly not because of barbed end monomer addition. ATP-G-actin levels decreased rapidly during depletion, but there was no change in the concentration of ADP-G-actin monomers. The decrease in ATP-G-actin levels could be accounted for by dissociation of the thymosin-G-actin binary complex, resulting in a rise in the concentration of free thymosin beta4 from 4 to 11 microm. Increased detection of profilin-actin complexes during depletion indicated that profilin may participate in catalyzing nucleotide exchange during depletion. This mechanism provides a biochemical basis for the accumulation of F-actin aggregates in ischemic cells.
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PMID:Mechanism of actin polymerization in cellular ATP depletion. 1462 92

Ischemia, absence or loss of blood flow in organs always presents as a dual phenomenon: tissue oxygen deficit and CO(2) excess (hypercapnia). Commonly hypoxic cell culture models kept CO(2) at normal nonischemic values. We report a study of apoptosis in an in vitro model of renal hypoxia that mimics in vivo tissue gas atmosphere composition determined during experimental ischemia in rat kidney (low O(2) plus high CO(2)). Renal tubular LLC-PK1 cell were transiently exposed to hypoxia, to hypercapnia or to both conditions (simulated ischemia). Exposure to simulated ischemic atmosphere, but not to low O(2) or high CO(2) alone, induced cell apoptosis in vitro. This suggests that ischemia-induced apoptosis in vivo would be dependent on the natural, joint action of hypoxia and hypercapnia. This should be taken into account in cell culture studies that would like to mimic in vivo ischemic conditions.
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PMID:Low O2 and high CO2 in LLC-PK1 cells culture mimics renal ischemia-induced apoptosis. 1468 98

The Ets family of transcription factors is defined by a conserved DNA-binding Ets domain that forms a winged helix-turn-helix structure motif. The Ets family is involved in a diverse array of biologic functions, including cellular growth, migration, and differentiation. The hypothesis in this study was that Ets-1 is re-expressed during regeneration after acute renal failure (ARF) and plays a key role in the transcriptional regulation of cyclin D1 and the cell cycle progression in renal tubular cells. For clarifying the significance of Ets-1 in ARF, a rat ARF model in vivo and LLC-PK1 cells as an in vitro model were used. After the left rat renal artery was clamped for 1 h, the whole kidney homogenate was examined and total RNA was extracted at 6, 12, 24, 48, and 72 h after reperfusion by Western blot analysis and real-time reverse transcription-PCR. Ets-1 mRNA and protein expression were strongly increased at 6 to 24 h after the ischemia, respectively. The expression of hypoxia-inducible factor-1alpha was increased dramatically as early as 6 h after ischemia-reperfusion and decreased at 48 and 72 h after ischemia-reperfusion. In the immunohistologic examination, Ets-1 was expressed in the proximal tubules and coexpressed with proliferating cell nuclear antigen (PCNA). Furthermore, overexpression of Ets-1 promoted the cell cycle and increased the promoter activity and protein expression of cyclin D1 in LLC-PK1 cells. Ets-1 promoter activity increased between 3 and 6 h in hypoxia, and hypoxia also induced changes in the Ets-1 protein level in LLC-PK1 cells. The Ets-1 induction by hypoxia was abolished by the transfection of dominant-negative hypoxia-inducible factor-1alpha. A gel shift assay demonstrated that Ets-1 binds to the ets-1 binding site of the cyclin D1 promoter in the ischemia-reperfusion condition. Overexpression of Ets-1 did not significantly change the caspase 3 activity or the value of cell death ELISA in LLC-PK1 cells. Taken together, these data suggest that Ets-1 plays a key role in the cell-cycle progression of renal tubules in ARF. The Ets-1 pathway may regulate the transcription of cyclin D1 and control the regeneration of renal tubules in ARF.
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PMID:Expression and function of Ets-1 during experimental acute renal failure in rats. 1557 11


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