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)

A key feature of the ischemic epithelial cell phenotype is the disruption of tight junctions (TJ). In a Manin-Darby canine kidney cell model for ischemia-reperfusion/hypoxia-reoxygenation injury which employs inhibitors of glycolysis (2-deoxy-D-glucose) and oxidative phosphorylation (antimycin A), transepithelial electrical resistance, a measure of TJ integrity, dropped rapidly, correlating well with declining ATP levels. Although immunocytochemical studies revealed only subtle changes in the distribution of the TJ proteins, zonula occludens (ZO)-1, ZO-2, and cingulin, examination of the Triton X-100 solubilities of these proteins, an indicator of cytoskeletal association, revealed a striking shift of all three TJ proteins into the insoluble pool, consistent with increased cytoskeletal interaction during ATP depletion. In addition, rate-zonal centrifugation analysis of a detergent-soluble fraction showed an increase in the amount of ZO-1 and ZO-2 in high density fractions following ATP depletion, providing further evidence for association of TJ proteins into a large complex possibly involving the cytoskeleton. Analysis of immunoprecipitation data from [35S]methionine-labeled cells revealed that ATP depletion led to the association of a 240-kDa protein with the ZO-1-containing complex. Western blots of this protein immunoprecipitated with anti-ZO-1 antibodies confirmed its identity as fodrin, a protein believed to link membrane and other proteins to the actin-based cytoskeleton. Together, our data suggest that in the absence of major immunocytochemical changes, ATP depletion leads TJ proteins to form large insoluble complexes and associate with the cytoskeleton. We propose a model in which a key, potentially regulated, step in the generation of the ischemic epithelial cell phenotype is the interaction between TJ proteins and fodrin and/or other cytoskeletal proteins.
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PMID:Tight junction proteins form large complexes and associate with the cytoskeleton in an ATP depletion model for reversible junction assembly. 919 9

Polarized epithelial cells separate two extremely different cellular milieus. The tight junction (TJ) is the most apical component of the junctional complex and serves as the permeability barrier between these environments. The tight junctional complex appears to be a dynamic and regulated structure. Some of its protein components have been identified and include the transmembrane protein occludin. Nontransmembrane proteins on the cytosolic leaflet including ZO-1, ZO-2, cingulin, 7H6, and several unidentified phosphoproteins are also believed to be part of the TJ. Interactions of some of these proteins with the actin cytoskeleton are a major determinant of TJ structure and may also play a role in the regulation of TJ assembly. Recent progress using the "calcium switch" and the "ATP depletion-repletion" model of TJ formation offers new insight regarding how these structures form. TJ biogenesis appears to be regulated, in part, by classic signal transduction pathways involving heterotrimeric G proteins, release of intracellular Ca2+, and activation of protein kinase C. Although many of the details of the signaling pathways have yet to be defined, these observations may provide insight into how TJs form during tubular development. Furthermore, it may be possible to suggest potential therapeutic targets for intervention in a variety of diseases (e.g., ischemia, toxic injury to the kidney and other epithelial tissue) where TJ integrity has been compromised and reassembly is required.
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PMID:Molecular structure and assembly of the tight junction. 945 17

H(2)O(2)-mediated elevation in endothelial solute permeability is associated with pathological events such as ischemia-reperfusion and inflammation. To understand how H(2)O(2) mediates increased permeability, we investigated the effects of H(2)O(2) administration on vascular endothelial barrier properties and tight junction organization and function. We report that H(2)O(2) exposure caused an increase in endothelial solute permeability in a time-dependent manner through extracellularly regulated kinase 1 and 2 (ERK1/ERK2) signal pathways. H(2)O(2) exposure caused the tight junctional protein occludin to be rearranged from endothelial cell-cell junctions. Occludin rearrangement involved redistribution of occludin on the cell surface and dissociation of occludin from ZO-1. Occludin also was heavily phosphorylated on serine residues upon H(2)O(2) administration. H(2)O(2) mediates changes in ERK1/ERK2 phosphorylation, increases endothelial solute permeability, and alters occludin localization and phosphorylation were all blocked by PD-98059, a specific mitogen-activated protein (MAP) or ERK kinase 1 inhibitor. These data strongly suggest that H(2)O(2)-mediated increased endothelial solute permeability involves the loss of endothelial tight junction integrity through increased ERK1/ERK2 activation.
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PMID:H(2)O(2)-mediated permeability: role of MAPK and occludin. 1089 13

Therapies that would accelerate recovery from ischemic injury could positively impact the number of kidneys procured from non-heart-beating donors. An acellular warm (32 degrees C) perfusion was used to deliver growth factors to canine kidneys damaged by 2 hours of warm ischemia. Fibroblast growth factors 1 and 2 were selected for activation of the tyrosine kinases because of their known receptor-specific binding in the kidney, metabolic regulation, and mitogenic effect. During 24 hours of ex vivo perfusion at near-normothermia, oxidative metabolism was sufficiently restored to the ischemically damaged tissue to support upregulation of cellular processes dependent on new synthesis. The junctional integrity protein, ZO-1 was used to determine recovery of cytoskeletal integrity. The upregulation of proliferating cell nuclear antigen was used as a marker for recovery of synthetic functions. This modulation of both injury and repair proteins in the damaged kidneys was dependent on new synthesis. The observed modulation resulting in normalization of the cytoskeletal integrity correlated with outcomes in that when the "repaired" kidneys were reimplanted, they provided life-sustaining function. In contrast, when warm ischemically damaged control kidneys without treatment, with subsequent hypothermic perfusion or warm perfused in the absence of growth factors, were reimplanted the result was nonviability. The results of this study suggest that the administration of growth factors during 24 hours of near-normothermic, acellular perfusion, in the absence of concordant inflammation, triggers pathways for new synthesis leading to cellular recovery rather than resulting in cell death.
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PMID:Potential of repairing ischemically damaged kidneys ex vivo. 1580 49

Although ischemia remains the leading cause of acute renal failure in humans, there is little information on the expression and activities of gelatinases of kidney glomeruli during ischemia-reperfusion injury. In this study, we used a unilateral ischemia-reperfusion model to investigate the activity and expression of gelatinases in glomeruli during acute ischemia. Unilateral ischemia was induced in rats by vascular clamping (30 min) followed by reperfusion (60 min) and isolation of glomeruli. The activity and expression of gelatinase proteins were determined by gelatin zymography and Western blotting. Gelatinase mRNA levels were evaluated by reverse transcriptase-PCR. Ischemia and reperfusion increased serum creatinine levels, hallmark of acute renal failure. Ischemia induced mRNA and protein MMP-2 expression. There was strong stimulation of MMP-9 mRNA, both forms of dimeric MMP-9, and active monomeric MMP-9. In contrast to TIMP-1 decreasing, TIMP-2 protein and mRNA increased during ischemia. During reperfusion, there was a gradual reversal of the MMP-2 and MMP-9 levels and a strong inhibition of TIMP-1 and TIMP-2 at the protein and mRNA levels. Endocytic receptor LRP was increased during ischemia and returned to normal during reperfusion. Expression of MMP-9 docking receptor CD-44 was increased during reperfusion. Finally, ZO-1, an in vivo MMP-9 substrate, was degraded during ischemia, revealing that MMP-9 upregulated during ischemia was functional. Our data suggest that stimulation of gelatinase activity during ischemia could contribute to glomeruli injury, providing new therapeutic targets for acute renal failure in humans. In contrast, elevated monomeric MMP-9 activity due to TIMP-1 decrease during reperfusion may participate to glomerular recovery.
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PMID:Ischemia-reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli. 1587 Aug 43

Hepatocyte growth factor (HGF) exerts its physiological activities as that of an organotropic factor for regeneration and can prevent ischemia-induced injuries; however, its effect and mechanism of action under in vivo pathophysiological conditions remains to be determined. Recently, we demonstrated that treatment with human recombinant HGF (hrHGF) attenuated the disruption of the blood-brain barrier (BBB) observed after microsphere embolism-induced sustained cerebral ischemia. To see if tight junctional proteins were involved in this attenuation, in the present study, we investigated the effects of HGF on the levels of occludin and zonula occludens (ZO)-1 in cerebrovascular endothelial cells after microsphere embolism. Sustained cerebral ischemia was induced by the injection of 700 microspheres (48 microm diameter) into the right internal carotid artery of rats. hrHGF was injected into the right ventricle of the brain by using an osmotic pump at a dose of 30 microg/7 days per animal. The levels of tight junctional proteins in the endothelial cells were examined by immunohistochemical analysis. Treatment with hrHGF attenuated the decrease in the expression of occludin and ZO-1 proteins in the endothelial cells that occurred after sustained cerebral ischemia. Furthermore, treatment with hrHGF resulted in retention of these tight junctional proteins in fluorescein isothiocyanate (FITC)-albumin-perfused cerebral vessels, which did not leak FITC-albumin in the ipsilateral cortex. These results suggest that HGF-mediated maintenance of the tight junctional proteins in the endothelial cells may be a possible mechanism for the protective effect of HGF against the disruption of the BBB after cerebral ischemia.
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PMID:Hepatocyte growth factor attenuates cerebral ischemia-induced increase in permeability of the blood-brain barrier and decreases in expression of tight junctional proteins in cerebral vessels. 1697 72

Sublethal renal ischemia induces tubular epithelium damage and kidney dysfunction. Using NRK-52E rat proximal tubular epithelial cells, we have established an in vitro model, which includes oxygen and nutrients deprivation, to study the proximal epithelial cell response to ischemia. By means of this system, we demonstrate that confluent NRK-52E cells lose monolayer integrity and detach from collagen IV due to: (i) actin cytoskeleton reorganization; (ii) Rac1 and RhoA activity alterations; (iii) Adherens junctions (AJ) and Tight junctions (TJ) disruption, involving redistribution but not degradation of E-cadherin, beta-catenin and ZO-1; (iv) focal adhesion complexes (FAC) disassembly, entangled by mislocalization of paxillin and FAK dephosphorylation. Reactive oxygen species (ROS) are generated during the deprivation phase and rapidly balanced at recovery involving MnSOD induction, among others. The use of antioxidants (NAC) prevented FAC disassembly by blocking paxillin redistribution and FAK dephosphorylation, without abrogating AJ or TJ disruption. In spite of this, NAC did not show any protective effect on cell detachment. H(2)O(2), as a pro-oxidant treatment, supported the contribution of ROS in tubular epithelial cell-matrix but not cell-cell adhesion alterations. In conclusion, ROS-mediated FAC disassembly was not sufficient for the proximal epithelial cell shedding in response to sublethal ischemia, which also requires intercellular adhesion disruption.
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PMID:Requirements for proximal tubule epithelial cell detachment in response to ischemia: role of oxidative stress. 1702 98

Cilostazol is a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3), which induces a vasodilatoric antiplatelet effect. In the present study, we investigated the impact of cilostazol on the blood-brain barrier (BBB), while focusing on the actin cytoskeleton (F-actin), the permeability of endothelial cells, and the junctional proteins under hypoxia/reoxygenation (H/R). Cilostazol was thus found to inhibit the cytoskeletal reorganization under H/R, in which F-actin decrease at the cell periphery. Accordingly, cilostazol was able to attenuate the hyperpermeability of endothelial cells in H/R to the level of the permeability in normoxia. However, the adherens junction (AJ) protein VE-cadherin was not preserved in the presence of cilostazol under H/R. On the other hand, beta-catenin was slightly retained by cilostazol. In contrast to the redistribution of these proteins, immunoblotting demonstrated the total amount of AJ and tight junction (TJ) proteins (occludin, ZO-1 and ZO-2) to not show any significant change under H/R stress in either the presence or absence of cilostazol. Taken together, cilostazol potently displayed a protective effect against acute ischemia by preventing an increase in the endothelial permeability through the preservation of the actin cytoskeleton and the redistribution of junctional proteins.
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PMID:Cilostazol inhibits the redistribution of the actin cytoskeleton and junctional proteins on the blood-brain barrier under hypoxia/reoxygenation. 1715 25

Hypertension is involved in the exacerbation of stroke. It is unclear how blood-brain barrier (BBB) tight-junction (TJ) and ion transporter proteins critical for maintaining brain homeostasis contribute to cerebral infarction during hypertension development. In the present study, we investigated cerebral infarct volume following permanent 4-h middle cerebral artery occlusion (MCAO) and characterized the expression of BBB TJ and ion transporter proteins in brain microvessels of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats at 5 wk (prehypertension), 10 wk (early-stage hypertension), and 15 wk (later-stage hypertension) of age. Hypertensive SHR show increased infarct volume following MCAO compared with WKY control rats. BBB TJ and ion transporter proteins, known to contribute to edema and fluid volume changes in the brain, show differential protein expression patterns during hypertension development. Western blot analysis of TJ protein zonula occludens-2 (ZO-2) showed decreased expression, while ion transporter, Na(+)/H(+) exchanger 1 (NHE-1), was markedly increased in hypertensive SHR. Expression of TJ proteins ZO-1, occludin, actin, claudin-5, and Na(+)-K(+)-2Cl(-) cotransporter remain unaffected in SHR compared with control. Selective inhibition of NHE-1 using dimethylamiloride significantly attenuated ischemia-induced infarct volume in hypertensive SHR following MCAO, suggesting a novel role for NHE-1 in the brain in the regulation of ischemia-induced infarct volume in SHR.
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PMID:Comparative changes in the blood-brain barrier and cerebral infarction of SHR and WKY rats. 1723 53

Dysfunction of tight junctions (TJs), located at the most apical part of the intestinal epithelium, is believed to result in various complications in intestinal disease. However, the behaviors of multiple kinds of TJ proteins during ischemia-reperfusion injury are not understood in detail. To determine changes in expression and localization of TJ proteins during intestinal-barrier recovery, we induced intestinal ischemia-reperfusion injury in rats, measured mucosa-to-blood permeability of fluorescein isothiocyanate-dextran-4 kDa, and compared it with spatiotemporal changes of ZO-1, occludin, and claudin-1, -2, -3, -4, and -5 by immunoconfocal microscopy. At 1 hour post-reperfusion, villi were denuded and intestinal-barrier function was lost. From 6 to 24 hours post-reperfusion, villous epithelium was restored by cell migration, and barrier function together with reticular pattern expression of ZO-1, occludin, and claudin-1, -3, and -5, recovered time-dependently. To the contrary, after ischemia-reperfusion injury, the localized expression of claudin-2 and claudin-4 observed in the non-treated control was lost and replaced with broader expression from crypts to villi with increased basolateral claudin-4 expression in epithelial cells. These data demonstrated that recovery of intestinal barrier function is associated with expression of ZO-1, occludin, and claudin-1, -3, and -5, whereas claudin-2 and claudin-4 show unique changes in expression and localization.
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PMID:Different changes in the expression of multiple kinds of tight-junction proteins during ischemia-reperfusion injury of the rat ileum. 1737 8


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